Cyclic benzimidazole derivatives useful as anti-diabetic agents

ABSTRACT

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2009/061132, filed Oct. 19, 2009,which claims priority from and the benefit of U.S. ProvisionalApplication No. 61/197,606, filed Oct. 29, 2008.

BACKGROUND OF THE INVENTION

Diabetes is characterized by elevated levels of plasma glucose(hyperglycemia) in the fasting state or after administration of glucoseduring an oral glucose tolerance test. In type 1 diabetes, orinsulin-dependent diabetes mellitus (IDDM), patients produce little orno insulin, the hormone which regulates glucose utilization. In Type 2diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin isstill produced by islet cells in the pancreas. Patients having Type 2diabetes have a resistance to the effects of insulin in stimulatingglucose and lipid metabolism in the main insulin-sensitive tissues,including muscle, liver and adipose tissues. These patients often havenormal levels of insulin, and may have hyperinsulinemia (elevated plasmainsulin levels), as they compensate for the reduced effectiveness ofinsulin by secreting increased amounts of insulin (Polonsky, Int. J.Obey. Relat. Metab. Disord. 24 Suppl 2:S29-31, 2000). Insulin resistanceis not primarily caused by a diminished number of insulin receptors butrather by a post-insulin receptor binding defect that is not yetcompletely understood. This lack of responsiveness to insulin results ininsufficient insulin-mediated activation of uptake, oxidation andstorage of glucose in muscle, and inadequate insulin-mediated repressionof lipolysis in adipose tissue and of glucose production and secretionin the liver. Eventually, a patient may be become diabetic due to theinability to properly compensate for insulin resistance. In humans, thebeta cells within the pancreatic islets initially compensate for insulinresistance by increasing insulin output. The onset of Type 2 diabetesdue to insufficient increases (or actual declines) in beta cell mass isapparently due to increased beta cell apoptosis relative to non-diabeticinsulin resistant individuals (Butler et al., Diabetes 52:102-110,2003).

Persistent or uncontrolled hyperglycemia is associated with increasedand premature morbidity and mortality. Often abnormal glucosehomeostasis is associated both directly and indirectly with obesity,hypertension, and alterations of the lipid, lipoprotein andapolipoprotein metabolism, as well as other metabolic and hemodynamicdisease. Patients with Type 2 diabetes mellitus have a significantlyincreased risk of macrovascular and microvascular complications,including atherosclerosis, coronary heart disease, stroke, peripheralvascular disease, hypertension, nephropathy, neuropathy, andretinopathy. Therefore, effective therapeutic control of glucosehomeostasis, lipid metabolism, obesity, and hypertension are criticallyimportant in the clinical management and treatment of diabetes mellitus.

Patients who have insulin resistance often exhibit several symptoms thattogether are referred to as syndrome X or metabolic syndrome. Patientswith metabolic syndrome have an increased risk of developingatherosclerosis and coronary heart disease.

There are several available treatments for Type 2 diabetes, each ofwhich has its own limitations and potential risks. Physical exercise anda reduction in dietary intake of calories often dramatically improve thediabetic condition and are the usual recommended first-line treatment ofType 2 diabetes and of pre-diabetic conditions associated with insulinresistance. Compliance with this treatment is generally very poorbecause of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of fat andcarbohydrates. Pharmacologic treatments for diabetes have largelyfocused on three areas of pathophysiology: (1) hepatic glucoseproduction (biguanides, such as phenformin and metformin), (2) insulinresistance (PPAR agonists, such as rosiglitazone, troglitazone,engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512,LY-818 and pioglitazone), (3) insulin secretion (sulfonylureas, such astolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics(GLP-1 derivatives and analogs, such as exenatide and liraglitide); and(5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, suchas sitagliptin).

Many of the current treatments for diabetes have unwanted side effects.Phenformin and metformin can induce lactic acidosis, nausea/vomiting,and diarrhea. Metformin has a lower risk of side effects than phenforminand is widely prescribed for the treatment of Type 2 diabetes. Thecurrently marketed PPAR gamma agonists are modestly effective inreducing plasma glucose and hemoglobin A1C, and do not greatly improvelipid metabolism or the lipid profile. Sulfonylureas and related insulinsecretagogues can cause insulin secretion even if the glucose level islow, resulting in hypoglycemia, which can be fatal in severe cases. Theadministration of insulin secretagogues must therefore be carefullycontrolled. There remains a need for treatments for diabetes that workby novel mechanisms of action and that exhibit fewer side effects.

AMP-activated protein kinase (AMPK) has been identified as a regulatorof carbohydrate and fatty acid metabolism that helps maintain energybalance in response to environmental and nutritional stress. There isevidence that activation of AMPK results in a number of beneficialeffects on lipid and glucose metabolism by reducing glucogenesis and denovo lipogenesis (fatty acid and cholesterol synthesis), and byincreasing fatty acid oxidation and skeletal muscle glucose uptake.Inhibition of ACC, by phosphorylation by AMPK, leads to a decrease infatty acid synthesis and to an increase in fatty acid oxidation, whileinhibition of HMG-CoA reductase, by phosphorylation by AMPK, leads to adecrease in cholesterol synthesis (Carling, D. et. al., FEBS Letters223:217 (1987)).

In the liver, AMPK activation results in a decrease in fatty acid andcholesterol synthesis, inhibiting hepatic glucose production andincreasing fatty acid oxidation. It has been shown that AMP-activatedprotein kinase regulates triacylglycerol synthesis and fatty acidoxidation in liver and muscle via glycerol-3-phosphate acyltransferase(Muoio, D. M. et. al., Biochem. J. 338:783 (1999)). Another substrace ofAMPK, hepatocyte nuclear factor-4α, has been shown to be involved intype-1 maturity onset diabetes (Leclerc, I. et. al., Diabetes 50:1515(2001)). Additional processes believed to be regulated through AMPKactivation include the stimulation of glucose transport in skeletalmuscle and the regulation of key genes in fatty acid and glucosemetabolism in the liver (Hardie, D. G. and Hawley, S. A., Bioessays 23:1112 (2001), Kemp, B. E. et al., Biochem. Soc. Transactions 31:162(2003), Musi, N. and Goodyear, L. J. Current Drug Targets-Immune,Endocrine and Metabolic Disorders 2:119 (2002); Lochhead, P. A. et. al.,Diabetes 49:896 (2000); and Zhou, G. et. al., J. of Clin. Invest. 108:1167 (2001).

In vivo studies have demonstrated the following beneficial effects ofboth acute and chronic administration of AICAR, an AMPK activator, inrodent models of obesity and type 2 diabetes: 1) an improvement inglucose homeostasis in insulin-resistant diabetic (ob/ob) mice; 2) adecrease in blood glucose concentrations in ob/ob and db/db mice and ablood glucose reduction of 35% following 8 weeks of administration; and3) a reduction in metabolic disturbances and a reduction of bloodpressure in rats displaying characteristics of insulin resistancesyndrome (Bergeron, R. et. al., Diabetes 50:1076 (2001); Song, S. M. et.al., Diabetologia 45:56 (2002); Halseth, A. E. et al., Biochem. andBiophys. Res. Comm. 294:798 (2002); and Buhl, E. S. et al., Diabetes 51:2199 (2002)). A further study of 7 week AICAR administration in obeseZucker (fa/fa) rats lead to a reduction in plasma triglycerides and freefatty acids; an increase in HDL cholesterol; and a normalization ofglucose metabolism as assessed by an oral glucose tolerance test(Minokoshi, Y. et. al., Nature 415: 339 (2002)). Expression of dominantnegative AMPK in skeletal muscle of transgenic mice has demonstratedthat the AICAR effect on stimulation of glucose transport is dependenton AMPK activation (Mu, J. et. al., Molecular Cell 7: 1085 (2001)).

Recent data also suggest that AMPK activation is involved in the glucoseand lipid-lowering effects of the anti-diabetic drug metformin. It hasbeen shown that the diabetes drug metformin can activate AMPK in vivo athigh concentrations (Zhou, G. et. al., J. of Clin. Invest. 108: 1167(2001); Musi, N. et. al. Diabetes 51: 2074 (2002)).

Based on these studies, it is expected that the in vivo activation ofAMPK in the liver may result in the reduction of hepatic glucose output,an improvement in overall glucose homeostasis, a decrease in fatty acidand cholesterol synthesis, and an increase in fatty acid oxidation.Stimulation of AMPK in skeletal muscle is expected to result in anincrease in glucose uptake and fatty acid oxidation with resultingimprovement of glucose homeostasis, and an improvement in insulinaction. Finally, the resulting increase in energy expenditure shouldlead to a decrease in body weight. The lowering of blood pressure hasalso been reported to be a consequence of AMPK activation.

Increased fatty acid synthesis is a characteristic of many tumor cells,therefore decreasing the synthesis of fatty acids via AMPK activationmay also be useful as a cancer therapy. Activation of AMPK may also beuseful to treat ischemic events in the brain (Blazquez, C. et. al., J.Neurochem. 73: 1674 (1999)); to prevent damage from reactive oxygenspecies (Zhou, M. et. al., Am. J. Physiol. Endocrinol. Metab. 279: E622(2000)); and to improve local circulatory systems (Chen, Z.-P., et. al.AMP-activated protein kinase phosphorylation of endothelial NO synthase.FEBS Letters 443: 285 (1999)).

Compounds that activate AMPK are expected to be useful to treat type 2diabetes mellitus, obesity, hypertension, dyslipidemia, cancer, andmetabolic syndrome, as well as cardiovascular diseases, such asmyocardial infarction and stroke, by improving glucose and lipidmetabolism and by reducing body weight. There is a need for potent AMPKactivators that have pharmacokinetic and pharmacodynamic propertiessuitable for use as human pharmaceuticals.

Benzimidazole compounds are disclosed in WO 93/07124; WO 95/29897; WO98/39342; WO 98/39343; WO 00/14095; WO 00/03997; WO 01/53272; WO01/53291; WO 02/092575; WO 02/40019; WO 03/018061; WO 05/002520; WO05/018672; WO 06/094209; U.S. Pat. No. 6,312,662; U.S. Pat. No.6,489,476; US 2005/0148643; DE 3 316 095; JP 6 298 731; EP 0 126 030; EP0 128 862; EP 0 129 506; and EP 0 120 403. AMPK activators are disclosedin WO 08/006,432; WO 05/051298; WO 05/020892; US 2007/015665; US2007/032529; US 2006/287356; and US 2005/038068.

SUMMARY OF THE INVENTION

The present invention is concerned with novel benzimidazole derivativesof structural Formula I:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are activators ofAMP-activated protein kinase (AMPK) and are useful in the treatment,prevention and suppression of diseases, disorders and conditionsmediated by activation of AMP-activated protein kinase, such as Type 2diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia,lipid disorders, obesity, hypertension, metabolic syndrome andatherosclerosis.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier. The present invention also relates to methods forthe treatment, control or prevention of disorders, diseases, andconditions responsive to activation of AMP-activated protein kinase in asubject in need thereof by administering the compounds andpharmaceutical compositions of the present invention. The presentinvention also relates to the use of compounds of the present inventionfor manufacture of a medicament useful in treating diseases, disordersand conditions responsive to the activation of AMP-activated proteinkinase. The present invention is also concerned with treatment of thesediseases, disorders and conditions by administering the compounds of thepresent invention in combination with a therapeutically effective amountof another agent known to be useful to treat the disease, disorder andcondition. The invention is further concerned with processes forpreparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof, wherein:X is absent or selected from:

(1) —S—,

(2) —O—,

(3) —NH—,

(4) —C(O)—,

(5) —NHC(O)—,

(6) —C(O)NH—,

(7) —NHSO₂—,

(8) —SO₂NH—, and

(9) —CO₂—,

wherein NH is unsubstituted or substituted with 1 substituent selectedfrom: —C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₆alkyl, —COC₁₋₆alkyl, phenyl and—CH₂phenyl;

Y is selected from:

(1) —CH₂—,

(2) —CH₂—CH₂—,

(3) —CH₂—CH₂—CH₂—,

(4) —CHF—, and

(5) —CF₂—,

wherein each CH₂ and CHF is unsubstituted or substituted with 1 or 2substituents selected from R^(b);

Z is selected from:

(1) —CN,

(2) —(CH₂)_(n)CO₂H,

(3) —(CH₂)_(n)CO₂R^(i),

(4) —(CH₂)_(n)OH,

(5) —(CH₂)_(n)C(O)NHR^(g),

(6) —(CH₂)_(n)NHC(O)C₁₋₆alkyl,

(7) —(CH₂)_(n)NHSO₂R^(i),

(8) —(CH₂)_(n)SO₂NHR^(g),

(9) —(CH₂)_(n)SO₂NHC(O)R^(i),

(10) —(CH₂)_(n)SO₂NHCO₂R^(i),

(11) —(CH₂)_(n)SO₂NHCON(R^(g))₂,

(12) —(CH₂)_(n)C(O)NHSO₂R^(i),

(13) —(CH₂)_(n)NHC(O)N(R^(g))₂,

(14) —(CH₂)_(n)C₃₋₁₀cycloalkyl-CO₂R^(e),

(15) heteroaryl,

(16) —C₂₋₁₀cycloheteroalkenyl, and

(17) —C₂₋₁₀cycloheteroalkyl,

wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from C₁₋₆alkyl, —OH and —NH₂, wherein each NH isunsubstituted or substituted with 1 substituent selected from R^(c), andwherein each alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from R^(c);each R¹ and R² is independently selected from:

(1) hydrogen,

(2) halogen,

(3) —CN,

(4) —CF₃,

(5) —C₁₋₆alkyl,

(6) —C₂₋₆alkenyl,

(7) —C₂₋₆alkynyl,

(8) —(CH₂)_(p)C₃₋₁₀cycloalkyl,

(9) —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,

(10) —(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl,

(11) —(CH₂)_(p)C₄₋₁₀cycloalkenyl,

(12) —(CH₂)_(p)C₄₋₇cycloalkenyl-aryl,

(13) —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,

(14) aryl,

(15) biphenyl,

(16) —(CH₂)_(p)heteroaryl,

(17) —C₂₋₆alkenyl-alkyl,

(18) —C₂₋₆alkenyl-aryl,

(19) —C₂₋₆alkenyl-heteroaryl,

(20) —C₂₋₆alkenyl-C₃₋₇cycloalkyl,

(21) —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,

(22) —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,

(23) —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,

(24) —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,

(25) —C₂₋₆alkynyl-alkyl,

(26) —C₂₋₆alkynyl-aryl,

(27) —C₂₋₆alkynyl-heteroaryl,

(28) —C₂₋₆alkynyl-C₃₋₇cycloalkyl,

(29) —C₂₋₆alkynyl-C₃₋₇cycloalkenyl,

(30) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,

(31) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and

(32) —(CH₂)_(p)C(O)phenyl,

wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl,alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² isselected from the group consisting of: hydrogen, halogen, —CN, —CF₃,—C₁₋₆alkyl, —C₂₋₆alkenyl and —C₂₋₆alkynyl, and provided that if R¹ or R²is hydrogen, then at least one of R³ and R⁴ is not hydrogen;R³ and R⁴ are each independently selected from:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₂₋₆alkenyl,

(5) —C₂₋₆alkynyl,

(6) —C₃₋₁₀cycloalkyl,

(7) —C₃₋₁₀cycloalkenyl,

(8) aryl,

(9) heteroaryl,

(10) —CN,

(11) —CF₃,

(12) —OH,

(13) —OC₁₋₆alkyl,

(14) —NH₂,

(15) —NHC₁₋₆alkyl,

(16) —N(C₁₋₆alkyl)₂,

(17) —SC₁₋₆alkyl,

(18) —SOC₁₋₆alkyl,

(19) —SO₂C₁₋₆alkyl,

(20) —NHSO₂C₁₋₆alkyl,

(21) —NHC(O)C₁₋₆alkyl,

(22) —SO₂NHC₁₋₆alkyl, and

(23) —C(O)NHC₁₋₆alkyl;

R⁵ is selected from:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —CH₂CO₂H, and

(4) —CH₂CO₂C₁₋₆alkyl;

each R^(a) is independently selected from the group consisting of:

(1) halogen,

(2) oxo,

(3) —(CH₂)_(m)OH,

(4) —(CH₂)_(m)N(R^(j))₂,

(5) —(CH₂)_(m)NO₂,

(6) —(CH₂)_(m)CN,

(7) —C₁₋₆alkyl,

(8) —(CH₂)_(m)CF₃,

(9) —(CH₂)_(m)OCF₃,

(10) —OCH₂OC₁₋₆alkyl,

(11) —O-aryl,

(12) —OCH₂-aryl,

(13) —(CH₂)_(m)C(═N—OH)N(R^(j))₂,

(14) —(CH₂)_(m)OC₁₋₆alkyl,

(15) —(CH₂)_(m)—O-aryl,

(16) —(CH₂)_(m)SC₁₋₆alkyl,

(17) —(CH₂)_(m)S(O)C₁₋₆alkyl,

(18) —(CH₂)_(m)S(O)₂C₁₋₆alkyl,

(19) —(CH₂)_(m)NHS(O)₂C₁₋₆alkyl,

(20) —(CH₂)_(m)C(O)R^(f),

(21) —(CH₂)_(m)C(O)N(R^(j))₂,

(22) —(CH₂)_(m)N(R^(j))C(O)R^(f),

(23) —(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂,

(24) —(CH₂)_(m)CO₂H,

(25) —(CH₂)_(m)OC(O)H,

(26) —(CH₂)_(m)CO₂R^(f),

(27) —(CH₂)_(m)OC(O)R^(f),

(28) —(CH₂)_(m)C₃₋₇cycloalkyl,

(29) —(CH₂)_(m)C₃₋₇cycloalkenyl,

(30) —(CH₂)_(m)C₂₋₆cycloheteroalkyl,

(31) —(CH₂)_(m)C₂₋₆cycloheteroalkenyl,

(32) —(CH₂)_(m)aryl, and

(33) —(CH₂)_(m)heteroaryl,

wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl;each R^(b) is independently selected from:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) halogen,

(4) —OH,

(5) —NO₂,

(6) —NH₂,

(7) —NH(C₁₋₆alkyl),

(8) —N(C₁₋₆alkyl)₂,

(9) —OC₁₋₆alkyl,

(10) —(CH₂)_(q)CO₂H,

(11) —(CH₂)_(q)CO₂C₁₋₆alkyl,

(12) —CF₃,

(13) —CN,

(14) —SO₂C₁₋₆alkyl, and

(15) —(CH₂)_(q)CON(R^(e))₂,

wherein each CH₂ is unsubstituted or substituted with 1 or 2 halogens,and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with 1, 2 or 3 halogens;

each R^(c) is independently selected from:

-   -   (1) halogen,    -   (2) oxo,    -   (3) —(CH₂)_(r)OH,    -   (4) —(CH₂)_(r)N(R^(e))₂,    -   (5) —(CH₂)_(r)CN,    -   (6) —C₁₋₆alkyl,    -   (7) —CF₃,    -   (8) —C₁₋₆alkyl-OH,    -   (9) —OCH₂OC₁₋₆alkyl,    -   (10) —(CH₂)_(r)OC₁₋₆alkyl,    -   (11) —OCH₂aryl,    -   (12) —(CH₂)_(r)SC₁₋₆alkyl,    -   (13) —(CH₂)_(r)C(O)R^(f),    -   (14) —(CH₂)_(r)C(O)N(R^(e))₂,    -   (15) —(CH₂)_(r)CO₂H,    -   (16) —(CH₂)_(r)CO₂R^(f),    -   (17) —(CH₂)_(r)C₃₋₇cycloalkyl,    -   (18) —(CH₂)_(r)C₂₋₆cycloheteroalkyl,    -   (19) —(CH₂)_(r)aryl, and    -   (20) —(CH₂)_(r)heteroaryl,        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,        —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,        —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein        alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1, 2, 3 or 4 substituents        selected from: oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl,        —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,        —C₃₋₇cycloalkyl and heteroaryl;        each R^(e), R^(g) and R^(h) is independently selected from:

(1) hydrogen, and

(2) C₁₋₆alkyl,

wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂;

each R^(j) is independently selected from:

(1) hydrogen,

(2) C₁₋₆alkyl,

(3) C₃₋₆cycloalkyl,

(4) —C(O)R^(i), and

(5) —SO₂R^(i),

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1, 2,3 or 4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,—OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂;

each R^(f) and R^(i) is independently selected from:

(1) C₁₋₆alkyl,

(2) C₄₋₇cycloalkyl,

(3) C₄₋₇cycloalkenyl,

(4) C₃₋₇cycloheteroalkyl,

(5) C₃₋₇cycloheteroalkenyl,

(6) aryl, and

(7) heteroaryl,

wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, and heteroaryl;n is 0, 1, 2, 3 or 4;m is 0, 1, 2, 3 or 4;p is 0, 1, 2, or 3;q is 0, 1, 2, 3 or 4; andr is 0, 1 ort.

In one embodiment X is absent or selected from: —S—, —O—, —NH—, —C(O)—,—NHC(O)—, —C(O)NH—, —NHSO₂—, —SO₂NH—, and —CO₂—, wherein NH isunsubstituted or substituted with 1 substituent selected from:—C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₆alkyl, —COC₁₋₆alkyl, phenyl and —CH₂phenyl.In a class of this embodiment, X is absent or selected from: —S—, —O—,—NH—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO₂—, —SO₂NH—, and —CO₂—. Inanother embodiment, X is absent. In another embodiment, X is absent orselected from: —S—, —O—, and —C(O)NH—, wherein NH is unsubstituted orsubstituted with 1 substituent selected from: —C₁₋₆alkyl, —CO₂H,—CO₂C₁₋₆alkyl, —COC₁₋₆alkyl, phenyl and —CH₂phenyl. In a class of thisembodiment, X is selected from: —S—, —O—, and —C(O)NH—, wherein NH isunsubstituted or substituted with 1 substituent selected from:—C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₆alkyl, —COC₁₋₆alkyl, phenyl and —CH₂phenyl.In another class of this embodiment, X is selected from: —S—, —O—, and—C(O)NH—. In another embodiment, X is absent or selected from: —S— and—O—. In another embodiment, X is absent or —S—. In another embodiment, Xis —S—. In another embodiment, X is absent or —O—. In anotherembodiment, X is —O—. In another embodiment of the present invention, Yis selected from: —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CHF—, and —CF₂—,wherein each —CH₂ and —CHF is unsubstituted or substituted with 1 or 2substituents selected from R^(b). In a class of this embodiment, Y isselected from: —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CHF—, and —CF₂—.

In another embodiment of the present invention, Y is selected from:—CH₂—, —CH₂—CH₂—, and —CH₂—CH₂—CH₂—, wherein each —CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from R^(b). In a classof this embodiment, Y is selected from: —CH₂—, —CH₂—CH₂—, and—CH₂—CH₂—CH₂—. In another class of this embodiment, Y is —CH₂—. Inanother class of this embodiment, Y is —CH₂—CH₂—. In another class ofthis embodiment, Y is —CH₂—CH₂—CH₂—. In another embodiment of thepresent invention, Y is selected from: —CH₂— and —CH₂—CH₂—, wherein each—CH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom R^(b). In a class of this embodiment, Y is selected from: —CH₂—,wherein CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from R^(b). In another class of this embodiment, Y is—CH₂—CH₂—, wherein each —CH₂ is unsubstituted or substituted with 1 or 2substituents selected from R^(b). In another class of this embodiment, Yis selected from: —CH₂— and —CH₂—CH₂—. In another class of thisembodiment, Y is —CH₂—. In another class of this embodiment, Y is—CH₂—CH₂—. In another embodiment of the present invention, Y is —CH₂—,wherein each —CH₂ is unsubstituted or substituted with 1 or 2substituents selected from R^(b). In a class of this embodiment, Y is—CH₂—. In another embodiment of the present invention, Y is —CH₂—CH₂—,wherein each —CH₂ is unsubstituted or substituted with 1 or 2substituents selected from R^(b). In a class of this embodiment, Y is—CH₂—CH₂—.

In another embodiment of the present invention, Z is selected from: —CN,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂R^(i), —(CH₂)_(n)OH, —(CH₂)_(n)C(O)NHR^(g),—(CH₂)_(n)NHC(O)C₁₋₆alkyl, —(CH₂)_(n)NHSO₂R^(i), —(CH₂)_(n)SO₂NHR^(g),—(CH₂)_(n)SO₂NHC(O)R^(i), —(CH₂)_(n)SO₂NHCO₂R^(i),—(CH₂)_(n)SO₂NHCON(R^(g))₂, —(CH₂)_(n)C(O)NHSO₂R^(i),—(CH₂)_(n)NHC(O)N(R^(g))₂, —(CH₂)_(n)C₃₋₁₀cycloalkyl-CO₂R^(e),heteroaryl, —C₂₋₁₀cycloheteroalkenyl, and —C₂₋₁₀cycloheteroalkyl,wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from C₁₋₆alkyl, —OH and —NH₂, wherein each NH isunsubstituted or substituted with 1 substituent selected from R^(c), andwherein each alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from R^(c). In another embodiment of the presentinvention, Z is selected from: —CN, —(CH₂)_(n)CO₂H, —CO₂R^(i), —OH,—(CH₂)_(n)C(O)NHR^(g), —NHC(O)C₁₋₆alkyl, —NHSO₂R^(i), —SO₂NHR^(g),—SO₂NHC(O)R^(i), —SO₂NHCO₂R^(i), —SO₂NHCON(R^(g))₂, —C(O)NHSO₂R^(i),NHC(O)N(R^(g))₂, —C₃₋₁₀cycloalkyl-CO₂R^(e), heteroaryl,—C₂₋₁₀cycloheteroalkenyl, and —C₂₋₁₀cycloheteroalkyl, wherein each CH₂is unsubstituted or substituted with 1 or 2 substituents selected fromC₁₋₆alkyl, —OH and —NH₂, wherein each NH is unsubstituted or substitutedwith 1 substituent selected from R^(c), and wherein each alkyl,cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents selected fromR^(c). In another embodiment of the present invention, Z is selectedfrom: —CN, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂R^(i), —(CH₂)_(n)OH,—(CH₂)_(n)C(O)NHR^(g), heteroaryl, and —C₂₋₁₀cycloheteroalkenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from C₁₋₆alkyl, —OH and —NH₂, wherein each NH is unsubstitutedor substituted with 1 substituent selected from R^(c), and wherein eachalkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from R^(c). In a class of this embodiment, Z isselected from: —CN, —CO₂H, —CO₂R^(i), —OH, —C(O)NHR^(g), heteroaryl, and—C₂₋₁₀cycloheteroalkenyl, wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c), and wherein eachalkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(c). In another class of this embodiment, Z is selectedfrom: —CN, —CO₂H, —CO₂R^(i), —OH, —C(O)NH₂, heteroaryl, and—C₂₋₁₀cycloheteroalkenyl, wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c), and wherein eachcycloheteroalkenyl and heteroaryl is unsubstituted or substituted with1, 2 or 3 substituents selected from R^(c). In another class of thisembodiment, Z is selected from: —CN, —CO₂H, —CO₂R^(i), —OH, —C(O)NH₂,tetrazole, and dihydrooxadiazole, wherein each cycloheteroalkenyl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(c).

In another embodiment of the present invention, Z is selected from:—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂R^(i), —(CH₂)_(n)C(O)NHR^(g), heteroaryl,and —C₂₋₁₀cycloheteroalkenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from C₁₋₆alkyl, —OH and—NH₂, wherein each NH is unsubstituted or substituted with 1 substituentselected from R^(c), and wherein each alkyl, cycloalkyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom R^(c). In a class of this embodiment, Z is selected from: —CO₂H,—CO₂R^(i), —C(O)NHR^(g), heteroaryl, and —C₂₋₁₀cycloheteroalkenyl,wherein each NH is unsubstituted or substituted with 1 substituentselected from R^(c), and wherein each cycloheteroalkenyl and heteroarylis unsubstituted or substituted with 1, 2 or 3 substituents selectedfrom R^(c). In a class of this embodiment, Z is selected from: —CO₂H,—C(O)NHR^(g), heteroaryl, and —C₂₋₁₀cycloheteroalkenyl, wherein each NHis unsubstituted or substituted with 1 substituent selected from R^(c),and wherein each cycloheteroalkenyl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents selected from R^(c). In anotherclass of this embodiment, Z is selected from: —CO₂H, —C(O)NH₂,heteroaryl, and —C₂₋₁₀cycloheteroalkenyl, wherein eachcycloheteroalkenyl and heteroaryl is unsubstituted or substituted with1, 2 or 3 substituents selected from R^(c). In a subclass of this class,Z is selected from: —CO₂H, —C(O)NH₂, tetrazole, and dihydrooxadiazole,wherein each cycloheteroalkenyl and heteroaryl is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from R^(c). In anotherclass of this embodiment, Z is selected from: heteroaryl, and—C₂₋₁₀cycloheteroalkenyl, wherein each cycloheteroalkenyl and heteroarylis unsubstituted or substituted with 1, 2 or 3 substituents selectedfrom R^(c). In a subclass of this class, Z is selected from: tetrazole,and dihydrooxadiazole, wherein each cycloheteroalkenyl and heteroaryl isunsubstituted or substituted with 1, 2, or 3 substituents selected fromR^(c).

In another embodiment of the present invention, Z is selected from:—(CH₂)_(n)CO₂H, and —(CH₂)_(n)C(O)NHR^(g), wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected fromC₁₋₆alkyl, —OH and —NH₂, and wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c). In a class of thisembodiment, Z is selected from: —CO₂H, and —C(O)NH₂. In anotherembodiment of the present invention, Z is —(CH₂)_(n)CO₂H, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom C₁₋₆alkyl, —OH and —NH₂. In another embodiment of the presentinvention, Z is —(CH₂)_(n)CO₂H. In another embodiment of the presentinvention, Z is —CO₂H.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₇cycloalkyl-aryl,—C₃₋₇cycloalkyl-heteroaryl, —C₄₋₁₀cycloalkenyl, —C₄₋₇cycloalkenyl-aryl,—C₄₋₇cycloalkenyl-heteroaryl, aryl, biphenyl, -heteroaryl,—C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl,—C₂₋₆alkenyl-C₃₋₇cycloalkyl, —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl and—C₂₋₆alkynyl, and provided that if R¹ or R² is hydrogen, then at leastone of R³ and R⁴ is not hydrogen. In a class of this embodiment, R¹ isselected from: —C₃₋₁₀cycloalkyl, —C₃₋₇cycloalkyl-aryl,—C₃₋₇cycloalkyl-heteroaryl, —C₄₋₁₀cycloalkenyl, —C₄₋₇cycloalkenyl-aryl,—C₄₋₇cycloalkenyl-heteroaryl, aryl, biphenyl, -heteroaryl,—C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl,—C₂₋₆alkenyl-C₃₋₇cycloalkyl, —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl and —C₂₋₆alkynyl, wherein each alkyl, alkenyl and alkynylis unsubstituted or substituted with 1, 2 or 3 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, provided that if R² is hydrogen, then at least oneof R³ and R⁴ is not hydrogen. In another class of this embodiment, eachR¹ and R² is independently selected from: hydrogen, halogen, aryl,biphenyl, -heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and halogen, and provided that if R¹ or R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In a subclass of thisclass, R¹ is selected from: aryl, biphenyl, -heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen and halogen, provided that if R² ishydrogen, then at least one of R³ and R⁴ is not hydrogen. In anothersubclass of this class, each R¹ and R² is independently selected from:hydrogen, Cl, Br, F phenyl, biphenyl, pyridine, thiophene, thiazole,indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen, Br, Cl and F, and provided that if R¹ or R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In a subclass of thissubclass, R¹ is selected from: phenyl, biphenyl, pyridine, thiophene,thiazole, indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen, Br, Cl and F, and provided that if R²is hydrogen, then at least one of R³ and R⁴ is not hydrogen.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl and—C₂₋₆alkynyl, and provided that if R¹ or R² is hydrogen, then at leastone of R³ and R⁴ is not hydrogen. In a class of this embodiment, R¹ isselected from: aryl, biphenyl, heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl and —C₂₋₆alkynyl, and provided that if R² is hydrogen, thenat least one of R³ and R⁴ is not hydrogen. In another class of thisembodiment, each R¹ and R² is independently selected from: hydrogen,halogen, aryl, biphenyl, heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and halogen, and provided that if R¹ or R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In a subclass of thisclass, R¹ is selected from: aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen and halogen, and provided that if R²is hydrogen, then at least one of R³ and R⁴ is not hydrogen. In anothersubclass of this class, each R¹ and R² is independently selected from:hydrogen, Cl, phenyl, biphenyl, pyridine, thiophene, thiazole, indole,indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, —CH₂C(O)phenyl, wherein each CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and Cl, and provided that if R¹ or R² is hydrogen, then atleast one of R³ and R⁴ is not hydrogen. In a subclass of this subclass,R¹ is selected from: phenyl, biphenyl, pyridine, thiophene, thiazole,indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, —CH₂C(O)phenyl, wherein each CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of hydrogen and Cl, and provided that if R² ishydrogen, then at least one of R³ and R⁴ is not hydrogen.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₇cycloalkyl-aryl,—C₃₋₇cycloalkyl-heteroaryl, —C₄₋₁₀cycloalkenyl, —C₄₋₇cycloalkenyl-aryl,—C₄₋₇cycloalkenyl-heteroaryl, aryl, biphenyl, -heteroaryl,—C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl,—C₂₋₆alkenyl-C₃₋₇cycloalkyl, —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl and —C₂₋₆alkynyl. In aclass of this embodiment, R¹ is independently selected from:—C₃₋₁₀cycloalkyl, —C₃₋₇cycloalkyl-aryl, —C₃₋₇cycloalkyl-heteroaryl,—C₄₋₁₀cycloalkenyl, —C₄₋₇cycloalkenyl-aryl,—C₄₋₇cycloalkenyl-heteroaryl, aryl, biphenyl, -heteroaryl,—C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl,—C₂₋₆alkenyl-C₃₋₇cycloalkyl, —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyland —C₂₋₆alkynyl, wherein each alkyl, alkenyl and alkynyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂. In another class of this embodiment, each R¹ and R² isindependently selected from: halogen, aryl, biphenyl, -heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is halogen. In a subclass of thisclass, R¹ is selected from: aryl, biphenyl, -heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is halogen. Inanother subclass of this class, each R¹ and R² is independently selectedfrom: Cl, Br, F phenyl, biphenyl, pyridine, thiophene, thiazole, indole,indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: Br, Cl and F. In a subclass of this subclass, R¹ is independentlyselected from: phenyl, biphenyl, pyridine, thiophene, thiazole, indole,indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of Br, Cl and F.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, —CN, —CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl and —C₂₋₆alkynyl. In aclass of this embodiment, R¹ is selected from: aryl, biphenyl,heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyland —C₂₋₆alkynyl. In another class of this embodiment, each R¹ and R² isindependently selected from: halogen, aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1 or 2 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from R^(a), provided that at least one of andonly one of R¹ and R² is halogen. In a subclass of this class, R¹ isselected from: aryl, biphenyl, heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1 or 2 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from R^(a), and R² is halogen. In anothersubclass of this class, each R¹ and R² is independently selected from:Cl, phenyl, biphenyl, pyridine, thiophene, thiazole, indole, indazole,benzofuran, benzodioxole, benzothiophene, —C₂alkynyl-CH₂—O-phenyl,—C₂alkynyl-phenyl, —C₂alkynyl-naphthalene, —C₂alkynyl-pyridine,—C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane, —C₂alkynyl-piperidine,—CH₂C(O)phenyl, wherein each CH₂ is unsubstituted or substituted with 1or 2 substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein eachcycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), provided that at least one of and only one of R¹and R² is Cl. In a subclass of this subclass, R¹ is selected from:phenyl, biphenyl, pyridine, thiophene, thiazole, indole, indazole,benzofuran, benzodioxole, benzothiophene, —C₂alkynyl-CH₂—O-phenyl,—C₂alkynyl-phenyl, —C₂alkynyl-naphthalene, —C₂alkynyl-pyridine,—C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane, —C₂alkynyl-piperidine,—CH₂C(O)phenyl, wherein each CH₂ is unsubstituted or substituted with 1or 2 substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein eachcycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), and R² is Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: hydrogen, halogen, aryl, biphenyl,—(CH₂)_(p)heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and halogen, and provided that if R¹ or R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In a class of thisembodiment, R¹ is selected from: aryl, biphenyl, —(CH₂)_(p)heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from R^(a), and R² is selected from the groupconsisting of: hydrogen and halogen, and provided that if R² ishydrogen, then at least one of R³ and R⁴ is not hydrogen. In anotherclass of this embodiment, each R¹ and R² is independently selected from:hydrogen, halogen, aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein eachalkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² isselected from the group consisting of: hydrogen and halogen, andprovided that if R¹ or R² is hydrogen, then at least one of R³ and R⁴ isnot hydrogen. In a subclass of this class, R¹ is selected from: aryl,biphenyl, heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein eachalkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), and R² is selected from the group consisting of hydrogen andhalogen, and provided that if R² is hydrogen, then at least one of R³and R⁴ is not hydrogen. In another class of this embodiment, each R¹ andR² is independently selected from: hydrogen, halogen, aryl, biphenyl,heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-pyridine, —C₂₋₆alkynyl-thiophene,—C₂alkynyl-C₃₋₇cycloalkyl, —C₂alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), provided that at least one of and only one of R¹and R² is selected from the group consisting of: hydrogen and halogen,and provided that if R¹ or R² is hydrogen, then at least one of R³ andR⁴ is not hydrogen. In a subclass of this class, R¹ is selected from:aryl, biphenyl, heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl,—C₂₋₆alkynyl-phenyl, —C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-pyridine,—C₂₋₆alkynyl-thiophene, —C₂alkynyl-C₃₋₇cycloalkyl,—C₂alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl,phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or3 substituents independently selected from R^(a), and R² is selectedfrom the group consisting of: hydrogen and halogen, and provided that ifR² is hydrogen, then at least one of R³ and R⁴ is not hydrogen. Inanother class of this embodiment, each R¹ and R² is independentlyselected from: hydrogen, Cl, phenyl, biphenyl, pyridine, thiophene,thiazole, indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and Cl, and provided that if R¹ or R² is hydrogen, then atleast one of R³ and R⁴ is not hydrogen. In a subclass of this class, R¹is selected from: phenyl, biphenyl, pyridine, thiophene, thiazole,indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), and R² is selected fromthe group consisting of: hydrogen and Cl, and provided that if R² ishydrogen, then at least one of R³ and R⁴ is not hydrogen.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, aryl, biphenyl,—(CH₂)_(p)heteroaryl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is halogen. In a class of thisembodiment, R¹ is selected from: aryl, biphenyl, —(CH₂)_(p)heteroaryl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkynyl is unsubstitutedor substituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is halogen. Inanother class of this embodiment, each R¹ and R² is independentlyselected from: halogen, aryl, biphenyl, heteroaryl,—C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein eachalkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² ishalogen. In a subclass of this class, R¹ is selected from: aryl,biphenyl, heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein eachalkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), and R² is halogen. In another class of this embodiment, each R¹and R² is independently selected from: halogen, aryl, biphenyl,heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl, —C₂₋₆alkynyl-phenyl,—C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-pyridine, —C₂₋₆alkynyl-thiophene,—C₂alkynyl-C₃₋₇cycloalkyl, —C₂alkynyl-C₂₋₇cycloheteroalkyl, and—(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), provided that at least one of and only one of R¹and R² is halogen. In a subclass of this class, R¹ is selected from:aryl, biphenyl, heteroaryl, —C₂₋₆alkynyl-CH₂—O-phenyl,—C₂₋₆alkynyl-phenyl, —C₂₋₆alkynyl-naphthalene, —C₂₋₆alkynyl-pyridine,—C₂₋₆alkynyl-thiophene, —C₂alkynyl-C₃₋₇cycloalkyl,—C₂alkynyl-C₂₋₇cycloheteroalkyl, and —(CH₂)_(p)C(O)phenyl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl,and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl,phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or3 substituents independently selected from R^(a), and R² is halogen. Inanother class of this embodiment, each R¹ and R² is independentlyselected from: Cl, phenyl, biphenyl, pyridine, thiophene, thiazole,indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is Cl. In a subclass of this class, R¹is selected from: phenyl, biphenyl, pyridine, thiophene, thiazole,indole, indazole, benzofuran, benzodioxole, benzothiophene,—C₂alkynyl-CH₂—O-phenyl, —C₂alkynyl-phenyl, —C₂alkynyl-naphthalene,—C₂alkynyl-pyridine, —C₂alkynyl-thiophene, —C₂alkynyl-cyclopentane,—C₂alkynyl-piperidine, and —CH₂C(O)phenyl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each cycloalkyl, cycloheteroalkyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), and R² is Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: hydrogen, halogen, aryl, biphenyl, and—C₂₋₆alkynyl-aryl, wherein each alkynyl is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach phenyl and aryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and halogen, and provided that if R¹ or R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In a class of thisembodiment, R¹ is selected from: aryl, biphenyl, and —C₂₋₆alkynyl-aryl,wherein each alkynyl is unsubstituted or substituted with 1 or 2substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each phenyland aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), and R² is selected from the groupconsisting of: hydrogen and halogen, provided that if R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen. In another class of thisembodiment, each R¹ and R² is independently selected from: hydrogen,halogen, phenyl, biphenyl, and —C₂₋₆alkynyl-phenyl, wherein each alkynylis unsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each phenyl and aryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² isselected from the group consisting of: hydrogen and halogen, andprovided that if R¹ or R² is hydrogen, then at least one of R³ and R⁴ isnot hydrogen. In a subclass of this class, R¹ is selected from: phenyl,biphenyl, and —C₂₋₆alkynyl-phenyl, wherein each alkynyl is unsubstitutedor substituted with 1 or 2 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,and wherein each phenyl and aryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from R^(a), and R² isselected from the group consisting of hydrogen and halogen, and providedthat if R² is hydrogen, then at least one of R³ and R⁴ is not hydrogen.In another subclass of this class, each R¹ and R² is independentlyselected from: hydrogen, Cl, phenyl, biphenyl, and —C₂alkynyl-phenyl,wherein each phenyl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is selected from the group consistingof: hydrogen and Cl, and provided that if R¹ or R² is hydrogen, then atleast one of R³ and R⁴ is not hydrogen. In a subclass of this subclass,R¹ is selected from: phenyl, biphenyl, and —C₂alkynyl-phenyl, whereineach phenyl is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from R^(a), and R² is selected from the groupconsisting of: hydrogen and Cl, and provided that if R² is hydrogen,then at least one of R³ and R⁴ is not hydrogen.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, aryl, biphenyl, and—C₂₋₆alkynyl-aryl, wherein each alkynyl is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach phenyl and aryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is halogen. In a class of thisembodiment, R¹ is selected from: aryl, biphenyl, and —C₂₋₆alkynyl-aryl,wherein each alkynyl is unsubstituted or substituted with 1 or 2substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each phenyland aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), and R² is halogen. In another classof this embodiment, each R¹ and R² is independently selected from:halogen, phenyl, biphenyl, and —C₂₋₆alkynyl-phenyl, wherein each alkynylis unsubstituted or substituted with 1 or 2 substituents selected from:halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂, and wherein each phenyl is unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from R^(a), providedthat at least one of and only one of R¹ and R² is halogen. In a subclassof this class, R¹ is selected from: phenyl, biphenyl, and—C₂₋₆alkynyl-phenyl, wherein each alkynyl is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each phenyl is unsubstituted or substituted with 1, 2 or 3substituents independently selected from R^(a), and R² is halogen. In asubclass of this class, each R¹ and R² is independently selected from:Cl, phenyl, biphenyl, and —C₂alkynyl-phenyl, wherein each phenyl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), provided that at least one of and only one of R¹and R² is Cl. In a subclass of this subclass, R¹ is independentlyselected from: phenyl, biphenyl, and —C₂alkynyl-phenyl, wherein eachphenyl is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from R^(a), and R² is Cl.

In another embodiment of the present invention, R¹ is selected from:phenyl and biphenyl, wherein each phenyl is unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from R^(a), and R² isselected from the group consisting of: hydrogen and halogen, andprovided that if R² is hydrogen, then at least one of R³ and R⁴ is nothydrogen. In another embodiment of the present invention, R¹ is selectedfrom: phenyl and biphenyl, wherein each phenyl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), and R² is Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, phenyl, biphenyl, heteroaryl, and—C₂alkynyl-phenyl, wherein each phenyl and heteroaryl is unsubstitutedor substituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² is Cl. Ina class of this embodiment, each R¹ and R² is independently selectedfrom: Cl, phenyl, biphenyl, indole, and —C₂alkynyl-phenyl, wherein eachphenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is halogen. In a class of thisembodiment, R¹ is independently selected from: phenyl, biphenyl,heteroaryl, and —C₂alkynyl-phenyl, wherein each phenyl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a), and R² is halogen. In a class of this embodiment,R¹ is selected from: phenyl, biphenyl, indole, and —C₂alkynyl-phenyl,wherein each phenyl and heteroaryl is unsubstituted or substituted with1 or 2 substituents independently selected from R^(a), and R² ishalogen.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: Cl, phenyl, biphenyl, heteroaryl, and—C₂alkynyl-phenyl, wherein each phenyl and heteroaryl is unsubstitutedor substituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² is Cl. Ina class of this embodiment, each R¹ and R² is independently selectedfrom: Cl, phenyl, biphenyl, indole, and —C₂alkynyl-phenyl, wherein eachphenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents independently selected from R^(a), provided that at leastone of and only one of R¹ and R² is Cl. In a class of this embodiment,R¹ is selected from: phenyl, biphenyl, heteroaryl, and—C₂alkynyl-phenyl, wherein each phenyl and heteroaryl is unsubstitutedor substituted with 1, 2 or 3 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² is Cl. Ina class of this embodiment, each R¹ and R² is independently selectedfrom: Cl, phenyl, biphenyl, indole, and —C₂alkynyl-phenyl, wherein eachphenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents independently selected from R^(a), and R² is Cl. In anotherclass of this embodiment, each R¹ and R² is independently selected from:Cl, phenyl, biphenyl, indole, and —C₂alkynyl-phenyl, wherein each phenyland heteroaryl is unsubstituted or substituted with 1 or 2 substituentsindependently selected from R^(a), provided that at least one of andonly one of R¹ and R² is Cl. In a subclass of this class, R¹ is selectedfrom: phenyl, biphenyl, indole, and —C₂alkynyl-phenyl, wherein eachphenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents selected from R^(a), and R² is Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: Cl, phenyl, biphenyl, and—C₂alkynyl-phenyl, wherein each phenyl is unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from R^(a), providedthat at least one of and only one of R¹ and R² is Cl. In a class of thisembodiment, R¹ is selected from: phenyl, biphenyl, and—C₂alkynyl-phenyl, wherein each phenyl is unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from R^(a), and R² isCl.

In another embodiment of the present invention, R³ and R⁴ are eachindependently selected from: hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl,heteroaryl, —CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl,—N(C₁₋₆alkyl)₂, —SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—NHSO₂C₁₋₆alkyl, —NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and—C(O)NHC₁₋₆alkyl. In a class of this embodiment, R³ and R⁴ are eachindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R³ and R⁴ are each independently selected from: hydrogen,F and Cl. In another subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen, and R⁴ is independently selected from:hydrogen and Cl. In a class of this embodiment, R³ and R⁴ are eachindependently selected from: hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂,—NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—NHSO₂C₁₋₆alkyl, —NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and—C(O)NHC₁₋₆alkyl. In a subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R³ and R⁴ are each independently selected from: hydrogen,F and Cl. In another subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen, and R⁴ is independently selected from:hydrogen and Cl. In another class of this embodiment, R³ and R⁴ are eachindependently selected from: hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂,—NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, and —SC₁₋₆alkyl. In a subclass of thisclass, R³ and R⁴ are each independently selected from: hydrogen, F, Brand Cl. In another subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen, F and Cl. In another subclass ofthis class, R³ and R⁴ are each independently selected from: hydrogen andCl. In another subclass of this class, R³ is hydrogen, and R⁴ isindependently selected from: hydrogen and Cl. In another class of thisembodiment, R³ and R⁴ are each independently selected from: hydrogen,halogen, and —C₁₋₆alkyl. In a subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R³ and R⁴ are each independently selected from: hydrogen,F and Cl. In another subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen and R⁴ is independently selected from:hydrogen and Cl.

In another embodiment of the present invention, R³ and R⁴ are eachindependently selected from: hydrogen and halogen. In a subclass of thisclass, R³ and R⁴ are each independently selected from: hydrogen, F, Brand Cl. In another subclass of this class, R³ and R⁴ are eachindependently selected from: hydrogen, F and Cl. In another subclass ofthis class, R³ and R⁴ are each independently selected from: hydrogen andCl. In another subclass of this class, R³ and R⁴ are both hydrogen. Inanother subclass of this class, R³ and R⁴ are both Cl. In anothersubclass of this class, R³ is hydrogen, and R⁴ is independently selectedfrom: hydrogen and halogen. In another subclass of this class, R³ ishydrogen, and R⁴ is independently selected from: hydrogen and Cl. Inanother subclass of this class, both R³ and R⁴ are hydrogen.

In another embodiment of the present invention, R³ is independentlyselected from: hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl, heteroaryl,—CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —NHSO₂C₁₋₆alkyl,—NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and —C(O)NHC₁₋₆alkyl. In a class ofthis embodiment, R³ is independently selected from: hydrogen, F, Br andCl. In another subclass of this class, R³ is independently selectedfrom: hydrogen, F and Cl. In another subclass of this class, R³ isindependently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen. In a class of this embodiment, R³ isindependently selected from: hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂,—NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—NHSO₂C₁₋₆alkyl, —NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and—C(O)NHC₁₋₆alkyl. In a class of this embodiment, R³ is independentlyselected from: hydrogen, F, Br and Cl. In another subclass of thisclass, R³ is independently selected from: hydrogen, F and Cl. In anothersubclass of this class, R³ is independently selected from: hydrogen andCl. In another subclass of this class, R³ is hydrogen. In another classof this embodiment, R³ is independently selected from: hydrogen,halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃, —OH,—OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, and —SC₁₋₆alkyl. In aclass of this embodiment, R³ is independently selected from: hydrogen,F, Br and Cl. In another subclass of this class, R³ is independentlyselected from: hydrogen, F and Cl. In another subclass of this class, R³is independently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen. In another class of this embodiment, R³ isindependently selected from: hydrogen, halogen, and —C₁₋₆alkyl. In asubclass of this class, R³ is independently selected from: hydrogen, F,Br and Cl. In another subclass of this class, R³ is independentlyselected from: hydrogen, F and Cl. In another subclass of this class, R³is independently selected from: hydrogen and Cl. In another subclass ofthis class, R³ is hydrogen.

In another embodiment of the present invention, R³ is independentlyselected from: hydrogen and halogen. In a subclass of this class, R³ isindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R³ is independently selected from: hydrogen, F and Cl. Inanother subclass of this class, R³ is independently selected from:hydrogen and Cl. In another subclass of this class, R³ is hydrogen. Inanother subclass of this class, R³ is Cl.

In another embodiment of the present invention, R⁴ is independentlyselected from: hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl, heteroaryl,—CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —NHSO₂C₁₋₆alkyl,—NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and —C(O)NHC₁₋₆alkyl. In a class ofthis embodiment, R⁴ is independently selected from: hydrogen, F, Br andCl. In another subclass of this class, R⁴ is independently selectedfrom: hydrogen, F and Cl. In another subclass of this class, R⁴ isindependently selected from: hydrogen and Cl. In another subclass ofthis class, R⁴ is hydrogen. In another subclass of this class, R⁴ is Cl.In a class of this embodiment, R⁴ is independently selected from:hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃,—OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —SC₁₋₆alkyl,—SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —NHSO₂C₁₋₆alkyl, —NHC(O)C₁₋₆alkyl,—SO₂NHC₁₋₆alkyl, and —C(O)NHC₁₋₆alkyl. In a subclass of this class, R⁴is independently selected from: hydrogen, F, Br and Cl. In anothersubclass of this class, R⁴ is independently selected from: hydrogen, Fand Cl. In another subclass of this class, R⁴ is independently selectedfrom: hydrogen and Cl. In another subclass of this class, R⁴ ishydrogen. In another subclass of this class, R⁴ is Cl. In another classof this embodiment, R⁴ is independently selected from: hydrogen,halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —CF₃, —OH,—OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, and —SC₁₋₆alkyl. In asubclass of this class, R⁴ is independently selected from: hydrogen, F,Br and Cl. In another subclass of this class, R⁴ is independentlyselected from: hydrogen, F and Cl. In another subclass of this class, R⁴is independently selected from: hydrogen and Cl. In another subclass ofthis class, R⁴ is hydrogen. In another subclass of this class, R⁴ is Cl.In another class of this embodiment, R⁴ is independently selected from:hydrogen, halogen, and —C₁₋₆alkyl. In a subclass of this class, R⁴ isindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R⁴ is independently selected from: hydrogen, F and Cl. Inanother subclass of this class, R⁴ is independently selected from:hydrogen and Cl. In another subclass of this class, R⁴ is hydrogen. Inanother subclass of this class, R⁴ is Cl.

In another embodiment of the present invention, R⁴ is independentlyselected from: hydrogen, and halogen. In a subclass of this class, R⁴ isindependently selected from: hydrogen, F, Br and Cl. In another subclassof this class, R⁴ is independently selected from: hydrogen, F and Cl. Inanother subclass of this class, R⁴ is independently selected from:hydrogen and Cl. In another subclass of this class, R⁴ is hydrogen. Inanother subclass of this class, R⁴ is Cl.

In another embodiment of the present invention, R⁵ is selected from:hydrogen, —C₁₋₆alkyl, —CH₂CO₂H, and —CH₂CO₂C₁₋₆alkyl. In anotherembodiment of the present invention, R⁵ is selected from: hydrogen,—CH₂CO₂H, and —CH₂CO₂C₁₋₆alkyl. In another embodiment of the presentinvention, R⁵ is selected from: hydrogen, and —C₁₋₆alkyl. In anotherembodiment of the present invention, R⁵ is —C₁₋₆alkyl. In anotherembodiment of the present invention, R⁵ is hydrogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: halogen, oxo,—(CH₂)_(m)OH, —(CH₂)_(m)N(R^(j))₂, —(CH₂)_(m)NO₂, —(CH₂)_(m)CN,—C₁₋₆alkyl, —(CH₂)_(m)CF₃, —(CH₂)_(m)OCF₃, —OCH₂OC₁₋₆alkyl, —OCH₂-aryl,—(CH₂)_(m)C(═N—OH)N(R^(j))₂, —(CH₂)_(m)OC₁₋₆alkyl, —(CH₂)_(m)—O-aryl,—(CH₂)_(m)SC₁₋₆alkyl, —(CH₂)_(m)S(O)C₁₋₆alkyl, —(CH₂)_(m)S(O)₂C₁₋₆alkyl,—(CH₂)_(m)NHS(O)₂C₁₋₆alkyl, —(CH₂)_(m)C(O)R^(f),—(CH₂)_(m)C(O)N(R^(j))₂, —(CH₂)_(m)N(R^(j))C(O)R^(f),—(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂, —(CH₂)_(m)CO₂H, —(CH₂)_(m)OC(O)H,—(CH₂)_(m)CO₂R^(f), —(CH₂)_(m)OC(O)R^(f), —(CH₂)_(m)C₃₋₇cycloalkyl,—(CH₂)_(m)C₃₋₇cycloalkenyl, —(CH₂)_(m)C₂₋₆cycloheteroalkyl,—(CH₂)_(m)C₂₋₆cycloheteroalkenyl, —(CH₂)_(m)aryl, and—(CH₂)_(m)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl,heteroaryl and CH₂heteroaryl, and wherein alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylare unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl. In a class of this embodiment, each CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, and each alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of this class, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen, and each alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylis unsubstituted or substituted with 1, 2, or 3 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: halogen, oxo,—(CH₂)_(m)OH, —N(R^(j))₂, —NO₂, —CN, —C₁₋₆alkyl, —CF₃, —OCF₃,—OCH₂OC₁₋₆alkyl, —OCH₂-aryl, —C(═N—OH)N(R^(j))₂, —OC₁₋₆alkyl, —O-aryl,—SC₁₋₆alkyl, —S(O)C₁₋₆alkyl, —S(O)₂C₁₋₆alkyl, —NHS(O)₂C₁₋₆alkyl,—C(O)R^(f), —C(O)N(R^(j))₂, —(CH₂)_(m)N(R^(j))C(O)R^(f),—N(R^(j))C(O)N(R^(j))₂, —CO₂H, —OC(O)H, —CO₂R^(f), —OC(O)R^(f),—C₃₋₇cycloalkyl, —C₃₋₇cycloalkenyl, —C₂₋₆cycloheteroalkyl,—C₂₋₆cycloheteroalkenyl, aryl, and heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl, andwherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl,CH₂phenyl, heteroaryl and CH₂heteroaryl. In a class of this embodiment,each CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl, and each alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and—CO₂C₁₋₆alkyl. In a subclass of this class, each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—C₁₋₆alkyl and halogen, and each alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, or 3 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen. In another class of thisembodiment, each R^(a) is independently selected from the groupconsisting of: halogen, —(CH₂)_(m)OH, —N(R^(j))₂, —NO₂, —CN, —C₁₋₆alkyl,—CF₃, —OCH₂-phenyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —S(O)C₁₋₆alkyl,—S(O)₂C₁₋₆alkyl, —NHS(O)₂C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂, —(CH₂)_(m)N(R^(j))C(O)C₁₋₆alkyl,—N(R^(j))C(O)phenyl, —N(R^(j))C(O)NHC₁₋₆alkyl, —CO₂H,—C₂₋₆cycloheteroalkyl, phenyl, and heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, andwherein alkyl, cycloheteroalkyl, phenyl, and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and—CO₂C₁₋₆alkyl. In a subclass of this class, each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—C₁₋₆alkyl and halogen, and each alkyl, cycloheteroalkyl, phenyl, andheteroaryl is unsubstituted or substituted with 1, 2, or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen. In anothersubclass of this class, each R^(a) is independently selected from thegroup consisting of: F, Cl, Br, —OH, —CH₂OH, —NH₂, —NO₂, —CN, methyl,ethyl, isobutyl, —CF₃, —OCH₂-phenyl, —OCH₃, —SCH₃, —S(O)CH₃, —SO₂CH₃,—NHSO₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —NHC(O)CF₁₃, —CH₂NHC(O)CH₃,—NHC(O)phenyl, —NHC(O)NHCH₂CH₃, —CO₂H, piperidine, morpholine, phenyl,and pyrazole, pyrazine, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkyl,cycloheteroalkyl, phenyl, and heteroaryl are unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo,—(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In asubclass of this subclass, each CH₂ is unsubstituted or substituted with1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl andhalogen, and each alkyl, cycloheteroalkyl, phenyl, and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)CF₃,—(CH₂)_(m)OCF₃, —OCH₂OC₁₋₆alkyl, —OCH₂-aryl,—(CH₂)_(m)C(═N—OH)N(R^(j))₂, —(CH₂)_(m)OC₁₋₆alkyl, —(CH₂)_(m)—O-aryl,—(CH₂)_(m)SC₁₋₆alkyl, —(CH₂)_(m)S(O)C₁₋₆alkyl, —(CH₂)_(m)S(O)₂C₁₋₆alkyl,—(CH₂)_(m)NHS(O)₂C₁₋₆alkyl, —(CH₂)_(m)C(O)R^(f),—(CH₂)_(m)C(O)N(R^(j))₂, —(CH₂)_(m)N(R^(j))C(O)R^(f),—(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂, —(CH₂)_(m)CO₂H,—(CH₂)_(m)C₃₋₇cycloalkyl, —(CH₂)_(m)C₃₋₇cycloalkenyl,—(CH₂)_(m)C₂₋₆cycloheteroalkyl, —(CH₂)_(m)C₂₋₆cycloheteroalkenyl,—(CH₂)_(m)aryl, and —(CH₂)_(m)heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, andwherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In a class of thisembodiment, each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen,and each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyland halogen. In another class of this embodiment, each R^(a) isindependently selected from the group consisting of: —CF₃, —OCH₂-phenyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —S(O)C₁₋₆alkyl, —S(O)₂C₁₋₆alkyl,—NHS(O)₂C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆alkyl)₂,—CH₂N(R^(j))C(O)C₁₋₆alkyl, —N(R^(j))C(O)phenyl,—N(R^(j))C(O)NHC₁₋₆alkyl, —CO₂H, —C₂₋₆cycloheteroalkyl, phenyl,heteroaryl, wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkyl, cycloheteroalkyl, phenyland heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of this class, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen, and each alkyl,cycloheteroalkyl, phenyl, and heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyland halogen. In another subclass of this class, each R^(a) isindependently selected from the group consisting of: —CF₃, —OCH₂-phenyl,—OCH₃, —SCH₃, —S(O)CH₃, —SO₂CH₃, —NHSO₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃,—NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)phenyl, —NHC(O)NHCH₂CH₃, —CO₂H,piperidine, morpholine, phenyl, pyrazole, pyrazine, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, andwherein alkyl, cycloheteroalkyl, phenyl, and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and—CO₂C₁₋₆alkyl. In a subclass of this subclass, each CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—C₁₋₆alkyl and halogen, and each alkyl, cycloheteroalkyl, phenyl, andheteroaryl is unsubstituted or substituted with 1, 2, or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of —(CH₂)_(m)CF₃,—OCH₂-aryl, —(CH₂)_(m)OC₁₋₆alkyl, —(CH₂)_(m)SC₁₋₆alkyl,—(CH₂)_(m)S(O)C₁₋₆alkyl, —(CH₂)_(m)S(O)₂C₁₋₆alkyl,—(CH₂)_(m)NHS(O)₂C₁₋₆alkyl, —(CH₂)_(m)C(O)N(R^(j))₂,—(CH₂)_(m)N(R^(j))C(O)R^(f), —(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂,—(CH₂)_(m)C₂₋₆cycloheteroalkyl, —(CH₂)_(m)aryl, and—(CH₂)_(m)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkyl,cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In a class of thisembodiment, each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen,and each alkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstitutedor substituted with 1, 2, or 3 substituents selected from: oxo,—(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen. In another class of thisembodiment, each R^(a) is independently selected from the groupconsisting of: —CF₃, —OCH₂-phenyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—S(O)C₁₋₆alkyl, —S(O)₂C₁₋₆alkyl, —NHS(O)₂C₁₋₆alkyl, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂, —(CH₂)_(m)N(R^(j))C(O)C₁₋₆alkyl,—N(R^(j))C(O)phenyl, —N(R^(j))C(O)NHC₁₋₆alkyl, —C₂₋₆cycloheteroalkyl,-phenyl, -heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkyl,cycloheteroalkyl, c phenyl and heteroaryl are unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo,—(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In asubclass of this class, each CH₂ is unsubstituted or substituted with 1or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl andhalogen, and each alkyl, cycloheteroalkyl, phenyl, and heteroaryl isunsubstituted or substituted with 1, 2, or 3 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen. In another subclass of thisclass, each R^(a) is independently selected from the group consistingof: —CF₃, —OCH₂-phenyl, —OCH₃, —SCH₃, —S(O)CH₃, —SO₂CH₃, —NHSO₂CH₃,—C(O)N(CH₃)₂, —C(O)NHCH₃, —NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)phenyl,—NHC(O)NHCH₂CH₃, piperidine, morpholine, phenyl, pyrazole, pyrazine,wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl, and wherein alkyl, cycloheteroalkyl, phenyl,and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of this subclass, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen, and each alkyl,cycloheteroalkyl, phenyl, and heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 substituents selected from: oxo,—(CH₂)₀₋₃OH, —C₁₋₆alkyl and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of halogen,—(CH₂)_(m)OH, —N(R^(j))₂, —NO₂, —CN, —C₁₋₆alkyl, —CF₃, —OCH₂-aryl,—O-aryl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —S(O)C₁₋₆alkyl, —S(O)₂C₁₋₆alkyl,—NHS(O)₂C₁₋₆alkyl, —C(O)N(R^(j))₂, —(CH₂)_(m)N(R^(j))C(O)R^(f),—N(R^(j))C(O)N(R^(j))₂, —CO₂H, —C₂₋₆cycloheteroalkyl, aryl, andheteroaryl, wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl, and wherein alkyl, cycloheteroalkyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2 or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl. In a class of this embodiment, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In another classof this embodiment, each CH₂ is unsubstituted, and each alkyl,cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substitutedwith 1 or 2 substituents selected from: —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. Inanother class of this embodiment, each R^(a) is independently selectedfrom the group consisting of halogen, —(CH₂)_(m)OH, —N(R^(j))₂, —NO₂,—CN, —C₁₋₆alkyl, —CF₃, —OCH₂-phenyl, —O-phenyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —S(O)C₁₋₆alkyl, —S(O)₂C₁₋₆alkyl, —NHS(O)₂C₁₋₆alkyl,—C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆alkyl)₂, —(CH₂)_(m)N(R^(j))C(O)C₁₋₆alkyl,—N(R^(j))C(O)phenyl, —N(R^(j))C(O)NHC₁₋₆alkyl, —CO₂H,—C₂₋₆cycloheteroalkyl, phenyl, and heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, andwherein alkyl, cycloheteroalkyl, phenyl and heteroaryl are unsubstitutedor substituted with 1, 2 or 3 substituents selected from: oxo,—(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl. In aclass of this embodiment, each CH₂ is unsubstituted or substituted with1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH, and —C₁₋₆alkyl, andeach alkyl, cycloheteroalkyl, phenyl and heteroaryl is unsubstituted orsubstituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, andhalogen. In another class of this embodiment, each CH₂ is unsubstituted,and each alkyl, cycloheteroalkyl, phenyl and heteroaryl is unsubstitutedor substituted with 1 or 2 substituents selected from: —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, andhalogen. In another class of this embodiment, each R^(a) isindependently selected from the group consisting of: F, Cl, Br, —OH,—CH₂OH, —NH₂, —NO₂, —CN, -methyl, ethyl, isobutyl, —CF₃, —OCH₂-phenyl,—O-phenyl, —OCH₃, —SCH₃, —S(O)CH₃, —SO₂CH₃, —NHSO₂CH₃, —C(O)N(CH₃)₂,—C(O)NHCH₃, —NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)phenyl, —NHC(O)NHCH₂CH₃,—CO₂H, piperidine, morpholine, phenyl, pyrazole, and pyrazine, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl, and wherein alkyl, cycloheteroalkyl, phenyl andheteroaryl are unsubstituted or substituted with 1, 2 or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl. In a subclass of this class, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl,phenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In anothersubclass of this class, each CH₂ is unsubstituted, and each alkyl,cycloheteroalkyl, phenyl and heteroaryl is unsubstituted or substitutedwith 1 or 2 substituents selected from: —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: F, Cl, —OH, —CH₂OH,—NH₂, —CN, -methyl, isobutyl, —OCH₂-phenyl, O-phenyl, —OCH₃, —SO₂CH₃,—NHSO₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —NHC(O)CH₃, —CH₂NHC(O)CH₃, phenyl,and pyrazole, wherein each CH₂ is unsubstituted or substituted with 1 or2 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, and wherein alkyl, cycloheteroalkyl,phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl. In a class of this embodiment, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl,phenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In another classof this embodiment, each CH₂ is unsubstituted, and each alkyl,cycloheteroalkyl, phenyl and heteroaryl is unsubstituted or substitutedwith 1 or 2 substituents selected from: —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)OH,—(CH₂)_(m)aryl, and —(CH₂)_(m)heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl, andwherein aryl and heteroaryl are unsubstituted or substituted with 1, 2or 3 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In a class of this embodiment,each CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, and —C₁₋₆alkyl, and each aryl andheteroaryl is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In another classof this embodiment, each CH₂ is unsubstituted, and each aryl andheteroaryl is unsubstituted or substituted with 1 or 2 substituentsselected from: —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In another class of thisembodiment, each R^(a) is independently selected from the groupconsisting of: —CH₂OH, phenyl, and pyrazole, wherein each phenyl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In a class of this embodiment, each phenyl andheteroaryl is unsubstituted or substituted with 1 or 2 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, and halogen. In another classof this embodiment, phenyl and heteroaryl is unsubstituted orsubstituted with 1 or 2 substituents selected from: —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, andhalogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)OH,—C₁₋₆alkyl, phenyl, and heteroaryl, wherein each alkyl, phenyl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl. In a class of this embodiment, each alkyl, phenyland heteroaryl is unsubstituted or substituted with 1 or 2 substituentsselected from: —OH, —C₁₋₆alkyl and halogen. In another class of thisembodiment, each alkyl, phenyl and heteroaryl is unsubstituted orsubstituted with 1 or 2 substituents selected from: —OH. In anotherclass of this embodiment, each R^(a) is independently selected from thegroup consisting of: —OH, —CH₂OH, methyl, phenyl, and pyrazole, whereineach alkyl, phenyl and heteroaryl is unsubstituted or substituted with1, 2 or 3 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl. In a class of this embodiment, eachalkyl, phenyl and heteroaryl is unsubstituted or substituted with 1 or 2substituents selected from: —OH, —C₁₋₆alkyl and halogen. In anotherclass of this embodiment, each alkyl, phenyl and heteroaryl isunsubstituted or substituted with 1 or 2 substituents selected from:—OH.

In another embodiment of the present invention, each R^(b) isindependently selected from: hydrogen, —C₁₋₆alkyl, halogen, —OH, —NO₂,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl, —(CH₂)_(q)CO₂H,—(CH₂)_(q)CO₂C₁₋₆alkyl, —CF₃, —CN, —SO₂C₁₋₆alkyl, and—(CH₂)_(q)CON(R^(e))₂, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 halogens, and wherein each alkyl is unsubstituted orsubstituted with 1, 2 or 3 halogens. In a class of this embodiment, eachR^(b) is independently selected from: hydrogen, —C₁₋₆alkyl, halogen,—OH, —NO₂, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl,—(CH₂)_(q)CO₂H, —(CH₂)_(q)CO₂C₁₋₆alkyl, —CF₃, —CN, —SO₂C₁₋₆alkyl, and—(CH₂)_(q)CON(R^(e))₂. In another embodiment of the present invention,each R^(b) is independently selected from: hydrogen, —C₁₋₆alkyl,halogen, —OH, —NO₂, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl,—CO₂H, —CO₂C₁₋₆alkyl, —CF₃, —CN, —SO₂C₁₋₆alkyl, and —CON(R^(e))₂,wherein each CH₂ is unsubstituted or substituted with 1 or 2 halogens,and wherein each alkyl is unsubstituted or substituted with 1, 2 or 3halogens. In a class of this embodiment, each R^(b) is independentlyselected from: hydrogen, —C₁₋₆alkyl, halogen, —OH, —NO₂, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl, —CO₂H, —CO₂C₁₋₆alkyl, —CF₃,—CN, —SO₂C₁₋₆alkyl, and —CON(R^(e))₂. In another embodiment of thepresent invention, each R^(b) is independently selected from: hydrogen,—C₁₋₆alkyl, halogen, —OH, —NO₂, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—OC₁₋₆alkyl, —CF₃, —CN, —SO₂C₁₋₆alkyl, and —(CH₂)_(q)CON(R^(e))₂,wherein each CH₂ is unsubstituted or substituted with 1 or 2 halogens,and wherein each alkyl is unsubstituted or substituted with 1, 2 or 3halogens. In a class of this embodiment, each R^(b) is independentlyselected from: hydrogen, —C₁₋₆alkyl, halogen, —OH, —NO₂, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl, —CF₃, —CN, —SO₂C₁₋₆alkyl,and —(CH₂)_(q)CON(R^(e))₂. In another embodiment of the presentinvention, each R^(b) is independently selected from: hydrogen,—C₁₋₆alkyl, halogen, —OH, —NO₂, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—OC₁₋₆alkyl, —CF₃, and —CN, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 halogens, and wherein each alkyl isunsubstituted or substituted with 1, 2 or 3 halogens. In a class of thisembodiment, each R^(b) is independently selected from: hydrogen,—C₁₋₆alkyl, halogen, —OH, —NO₂, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—OC₁₋₆alkyl, —CF₃, and —CN. In another embodiment of the presentinvention, each R^(b) is independently selected from: hydrogen, and—C₁₋₆alkyl, wherein each alkyl is unsubstituted or substituted with 1, 2or 3 halogens. In a class of this embodiment, each R^(b) isindependently selected from: hydrogen, and —C₁₋₆alkyl. In another classof this embodiment, each R^(b) is independently selected from: hydrogen,and methyl. In another class of this embodiment, each R^(b) is hydrogen.In another class of this embodiment, each R^(b) is methyl.

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH,—OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl,—(CH₂)_(r)C(O)R^(f), —(CH₂)_(r)C(O)N(R^(e))₂, —(CH₂)_(r)CO₂H,—(CH₂)_(r)CO₂R^(f), —(CH₂)_(r)C₃₋₇cycloalkyl,—(CH₂)_(r)C₂₋₆cycloheteroalkyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN,—N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl. In another embodiment ofthe present invention, each R^(c) is independently selected from:halogen, oxo, —(CH₂)_(r)OH, —(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN,—C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH, —OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl,—OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl, —(CH₂)_(r)C(O)R^(f),—(CH₂)_(r)C(O)N(R^(e))₂, —(CH₂)_(r)C₃₋₇cycloalkyl,—(CH₂)_(r)C₂₋₆cycloheteroalkyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —C₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1, 2 or 3 substituents selected from: oxo, —OH, —CN,—N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,and —CO₂C₁₋₆alkyl. In another embodiment of the present invention, eachR^(c) is independently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH,—OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl,—(CH₂)_(r)C(O)R^(f), and —(CH₂)_(r)C(O)N(R^(e))₂, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, andwherein alkyl and aryl are unsubstituted or substituted with 1, 2 or 3substituents selected from: oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, and—C₃₋₇cycloalkyl. In class of this embodiment, each R^(c) isindependently selected from: halogen, oxo, —OH, —N(R^(e))₂, —CN,—C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH, —OCH₂OC₁₋₆alkyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —C(O)R^(f), and —C(O)N(R^(e))₂, wherein alkyl isunsubstituted or substituted with 1, 2 or 3 substituents selected from:oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl.

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH,—OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl,—(CH₂)_(r)C(O)R^(f), —(CH₂)_(r)C(O)N(R^(e))₂, —(CH₂)_(r)CO₂H,—(CH₂)_(r)CO₂R^(f), —(CH₂)_(r)C₃₋₇cycloalkyl,—(CH₂)_(r)C₂₋₆cycloheteroalkyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl. In a class of this embodiment of the presentinvention, each R^(c) is independently selected from: halogen, oxo,—(CH₂)_(r)OH, —(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃,—C₁₋₆alkyl-OH, —OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl,—(CH₂)_(r)SC₁₋₆alkyl, —(CH₂)_(r)C(O)R^(f), —(CH₂)_(r)C(O)N(R^(e))₂,—(CH₂)_(r)C₃₋₇cycloalkyl, —(CH₂)_(r)C₂₋₆cycloheteroalkyl,—(CH₂)_(r)aryl, and —(CH₂)_(r)heteroaryl. In another class of thisembodiment, each R^(c) is independently selected from: halogen, oxo,—(CH₂)_(r)OH, —(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃,—C₁₋₆alkyl-OH, —OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl,—(CH₂)_(r)SC₁₋₆alkyl, —(CH₂)_(r)C(O)R^(f), and —(CH₂)_(r)C(O)N(R^(e))₂.In another class of this embodiment, each R^(c) is independentlyselected from: halogen, oxo, —(CH₂)_(r)OH, —(CH₂)_(r)N(R^(e))₂,—(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH, —(CH₂)_(r)OC₁₋₆alkyl,—(CH₂)_(r)SC₁₋₆alkyl, —(CH₂)_(r)C(O)R^(f), and —(CH₂)_(r)C(O)N(R^(e))₂.In another class of this embodiment, each R^(c) is independentlyselected from: halogen, oxo, —(CH₂)_(r)OH, —(CH₂)_(r)N(R^(e))₂,—(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH, —(CH₂)_(r)OC₁₋₆alkyl, and—(CH₂)_(r)SC₁₋₆alkyl. In another class of this embodiment, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, and —CF₃. In anotherclass of this embodiment, each R^(c) is independently selected from:halogen, oxo, and —C₁₋₆alkyl. In another embodiment of the presentinvention, each R^(c) is oxo.

In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of hydrogen, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl-OH,—(CH₂)_(r)C₃₋₇cycloalkyl, —(CH₂)_(r)C₂₋₆cycloheteroalkyl,—(CH₂)_(r)aryl, and —(CH₂)_(r)heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CO₂H, and —CO₂C₁₋₆alkyl, andwherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CO₂H, and—CO₂C₁₋₆alkyl. In a class of this embodiment, each R^(d) isindependently selected from the group consisting of hydrogen, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl-OH, wherein alkylis unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CO₂H, and—CO₂C₁₋₆alkyl. In another class of this embodiment, each R^(d) isindependently selected from the group consisting of —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, wherein alkyl is unsubstituted orsubstituted with 1, 2 or 3 substituents selected from —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CO₂H, and —CO₂C₁₋₆alkyl. In anotherclass of this embodiment, each R^(d) is independently selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, —C₁₋₆alkyl-OH, wherein alkylis unsubstituted or substituted with 1, 2 or 3 substituents selectedfrom —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CO₂H, and—CO₂C₁₋₆alkyl.

In another embodiment of the present invention, each R^(e), R^(g) andR^(h) is independently selected from: hydrogen, and C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsselected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂,—NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂. In a class of this embodiment, eachR^(e), R^(g) and R^(h) is independently selected from: hydrogen, andC₁₋₆alkyl. In another class of this embodiment, each R^(e) isindependently selected from: hydrogen, and C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂. In a class of this embodiment, each R^(e) isindependently selected from: hydrogen, and C₁₋₆alkyl. In another classof this embodiment, each R^(g) is independently selected from: hydrogen,and C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with 1, 2,3 or 4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,—OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂. In a class ofthis embodiment, each R^(g) is independently selected from: hydrogen,and C₁₋₆alkyl. In another class of this embodiment, each R^(h) isindependently selected from: hydrogen, and C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂. In a class of this embodiment, each R^(h) isindependently selected from: hydrogen, and C₁₋₆alkyl.

In another embodiment of the present invention, each R^(j) isindependently selected from: hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl,—C(O)R^(j), and —SO₂R^(j), wherein alkyl and cycloalkyl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂. In a class of this embodiment, each R^(j) isindependently selected from: hydrogen, —C₁₋₆alkyl, —C(O)R^(i), and—SO₂R^(i), wherein alkyl is unsubstituted or substituted with 1, 2, 3 or4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂. In another class of thisembodiment, each R^(j) is independently selected from: hydrogen, andC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3 or4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂. In another class of thisembodiment, each R^(j) is independently selected from: hydrogen andC₁₋₆alkyl.

In another embodiment of the present invention, each R^(f) and R^(i) isindependently selected from: C₁₋₆alkyl, C₄₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₃₋₇cycloheteroalkyl, C₃₋₇cycloheteroalkenyl, aryl,and heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, and heteroaryl. In aclass of this embodiment, each R^(f) and R^(i) is independently selectedfrom: C₁₋₆alkyl, C₄₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₃₋₇cycloheteroalkyl,C₃₋₇cycloheteroalkenyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylare unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In a class of this embodiment,each R^(f) is independently selected from: C₁₋₆alkyl, C₄₋₇cycloalkyl,C₄₋₇cycloalkenyl, C₃₋₇cycloheteroalkyl, C₃₋₇cycloheteroalkenyl, aryl,and heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, and heteroaryl. In asubclass of this class, each R^(f) is independently selected from:C₁₋₆alkyl, C₄₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₃₋₇cycloheteroalkyl,C₃₋₇cycloheteroalkenyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylare unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In another subclass of thisclass, each R^(f) is independently selected from: C₁₋₆alkyl, and phenyl,wherein alkyl and phenyl are unsubstituted or substituted with 1, 2, 3or 4 substituents selected from: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In asubclass of this subclass, each R^(f) is independently selected from:C₁₋₆alkyl, and phenyl. In another subclass of this subclass, each R^(f)is independently selected from: methyl, ethyl and phenyl.

In another class of this embodiment, R^(i) is independently selectedfrom: C₁₋₆alkyl, C₄₋₇cycloalkyl, C₄₋₇cycloalkenyl, C₃₋₇cycloheteroalkyl,C₃₋₇cycloheteroalkenyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylare unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, and heteroaryl. In asubclass of this class, R^(i) is independently selected from: C₁₋₆alkyl,and aryl, wherein alkyl and aryl are unsubstituted or substituted with1, 2, or 3 substituents selected from: oxo, —OH, —CN, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. In asubclass of this subclass, R^(i) is independently selected from:C₁₋₆alkyl, and phenyl, wherein alkyl and phenyl are unsubstituted orsubstituted with 1, 2, or 3 substituents selected from: oxo, —OH, —CN,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and—CO₂C₁₋₆alkyl. In another subclass of this subclass, R^(i) isindependently selected from: methyl, ethyl and phenyl.

In another embodiment of the present invention, n is 0, 1, 2, 3 or 4. Ina class of this embodiment, n is 1, 2 or 3. In another class of thisembodiment, n is 0, 1 or 2. In another class of this embodiment, n is 0.In another class of this embodiment, n is 1. In another class of thisembodiment, n is 2. In another embodiment of the present invention, m is0, 1, 2, 3, or 4. In a class of this embodiment, m is 1, 2 or 3. Inanother class of this embodiment, m is 0, 1 or 2. In another class ofthis embodiment, m is 0 or 1. In another class of this embodiment, m is0. In another class of this embodiment, m is 1. In another embodiment ofthe present invention, p is 0, 1, 2 or 3. In a class of this embodiment,p is 1, 2 or 3. In another class of this embodiment, p is 0, 1 or 2. Inanother class of this embodiment, p is 0 or 2. In another class of thisembodiment, p is 0. In another class of this embodiment, p is 1. Inanother class of this embodiment, p is 2. In another embodiment of thepresent invention, q is 0, 1, 2, 3 or 4. In a class of this embodiment,q is 1, 2 or 3. In another class of this embodiment, q is 0, 1 or 2. Inanother class of this embodiment, q is 1 or 2. In another class of thisembodiment, q is 0. In another class of this embodiment, q is 1. Inanother class of this embodiment, q is 2. In another embodiment of thepresent invention, r is 0, 1 or 2. In a class of this embodiment, r is 0or 1. In another class of this embodiment, r is 0. In another class ofthis embodiment, r is 1. In another class of this embodiment, r is 2. Inanother embodiment of the present invention, s is 0, 1, 2, 3 or 4. In aclass of this embodiment, s is 0, 1, 2 or 3. In a class of thisembodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0or 1. In another class of this embodiment, s is 1 or 2. In another classof this embodiment, s is 0 or 2. In another class of this embodiment, sis 0. In another class of this embodiment, s is 1. In another class ofthis embodiment, s is 2. In another class of this embodiment, s is 3.

The compound of structural formula I includes the compounds ofstructural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih and Ii:

wherein s is 0, 1 or 2;and pharmaceutically acceptable salts, hydrates and solvates thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as activators of AMP-protein kinase are thefollowing benzimidazoles.

or a pharmaceutically acceptable salt thereof.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains of up to 10 carbons which may belinear or branched or combinations thereof. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains up to 10 carbons which contain at leastone carbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like. In one embodiment of the presentinvention, alkenyl is vinyl.

“Alkynyl” means carbon chains up to 10 carbons which contain at leastone carbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like. In one embodiment of thepresent invention, alkynyl is ethynyl.

“Cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclicrings, each having from 3 to 14 carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and decahydronaphthyl, and the like. In one embodiment ofthe present invention, cycloalkyl is selected from cyclopentyl andcyclohexyl. In another embodiment of the present invention, cycloalkylis selected from cyclopropyl, cyclopentyl, and cyclohexyl.

“Cycloalkenyl” means nonaromatic, mono- or bicyclic or bridgedcarbocyclic rings, each having from 3 to 14 carbon atoms and containingat least one double bond. Examples of cycloalkyl include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl,decahydronaphthyl, bicyclo[2.2.1]hept-5-en-2-yl, and the like.

“Cycloheteroalkyl” means nonaromatic, mono- or bicyclic or bridgedsaturated carbocyclic rings, each having from 2 to 14 carbon atoms andcontaining 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S.Examples of cycloheteroalkyl include tetrahydrofuranyl, azetidinyl,perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl,1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl,imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl,dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl,thiomorpholinyl, dioxidoisothiazolidinyl, azacycloheptyl,diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. The cycloheteroalkylring may be substituted on the ring carbons and/or the ring nitrogens.In one embodiment of the present invention, cycloheteroalkyl is selectedfrom piperidine, pyrrolidine, oxazolidine, 1,3-oxazolidine-2,4-dione,thiazolidine, 1,3-thiazolidine-2,4-dione, imidazolidine, and hydantoin,and the like. In another embodiment of the present inventioncycloheteroalkyl is selected from: morpholine, pyrrolidine, piperazine,and piperidine. In another embodiment of the present invention,cycloheteroalkyl is imidazolidine.

“Cycloheteroalkenyl” means nonaromatic mono- or bicyclic or bridgedrings each having from 2 to 14 carbon atoms containing at least onedouble bond and containing 1, 2, 3, 4 or 5 heteroatoms selected from N,NH, O and S. Examples of cycloheteroalkenyl include1,2,4-oxadiazol-5-one, 1,2,4-thiadiazol-5-one, 1,2,4-triazol-3-one, and1,2,3,6-tetrahydropyridine, dihydro-1,3,4-oxadiazole, and[1,6]-dihydropyridine and the like. In one embodiment of the presentinvention, cycloheteroalkenyl is dihydro-1,3,4-oxadiazole. In anotherembodiment of the present invention, cycloheteroalkenyl is[1,6]-dihydropyridine.

“Aryl” means a monocyclic, bicyclic or tricyclic ring system containing5-14 carbon atoms, wherein at least one of the rings is aromatic. Arylthus includes ring systems in which an aromatic ring is fused to anon-aromatic ring, such as a cycloalkyl or cycloalkenyl ring. Examplesof aryl include phenyl, naphthalene, biphenyl, indane and5,6,7,8-tetrahydronaphthalene, and the like. In one embodiment of thepresent invention, aryl is phenyl, naphthalene, biphenyl, indane, and5,6,7,8-tetrahydronaphthalene. In another embodiment of the presentinvention, aryl is phenyl, naphthalene, indane and5,6,7,8-tetrahydronaphthalene. In one class of this embodiment, aryl isphenyl and naphthalene. In another class of this embodiment, aryl isphenyl. In another class of this embodiment, aryl is naphthalene.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic ring systemcontaining 5-14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatomsselected from N, NH, O and S wherein at least one of the heteroatomcontaining rings is aromatic. Heteroaryl thus includes ring systems inwhich an aromatic heteroatom containing ring is fused to a non-aromaticring, such as a cycloalkyl, cycloalkenyl, cycloheteroalkyl orcycloheteroalkenyl ring, and also includes ring systems in which an arylring is fused to a non-aromatic heteroatom containing ring, such asacycloheteroalkyl or cycloheteroalkenyl ring. Examples of heteroarylsinclude: pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene,benzoimidazole, quinoline, isoquinoline, indole, indazole, carbazole,benzotriazole, benzofuran, benzothiazole, benzothiophene,benzoisooxazole, oxazole, furan, benzoxazole, isoxazole, indoline,isoindoline, tetrazole, imidazole, oxadiazole, thiadiazole, triazole,benzothiazole, bernzopyrazole, imidazopyridine, benzodioxole,dihydropyridine, dihydropyrrolopyridine, dihydrobenzooxazine,benzodioxole, benzodioxine, pyrrolopyridine, triazolopyridine,dihydropyridooxazine, dihydrobenzoxazine, dihydroindole,dihydroisoindole, dihydrobenzoimidazole, dihydroquinoline,tetrahydroisoquinoline, tetrahydrocyclopentaindole,tetrahydroquinoxaline, and tetrahydropyridine. In one embodiment of thepresent invention, heteroaryl is selected from: imidazole, pyrazole,pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzoimidazole,quinoline, isoquinoline, indole, indazole, carbazole, benzotriazole,benzofuran, benzothiazole, benzo[b]thiophene, benzo[d]isooxazole,3,4-dihydro-2H-benzo[1,4]oxazine, benzo[1,3]dioxole, benzo[1,4]dioxine,1H-pyrrolo[2,3-b]pyridine, 1,6-dihydro-pyridine,[1,2,4]triazolo[4,3-a]pyridine, 3,4 dihydropyrido[3,2-b][1,4]oxazine,3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, 2,3-dihydrobenzoimidazole,1,2-dihydroquinoline, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydrocyclopenta[b]indole, 1,2,3,4-tetrahydroquinoxaline,and 1,2,3,6-tetrahydropyridine. In another embodiment of the presentinvention, heteroaryl is tetrazole. In another embodiment, heteroaryl isselected from: pyrazole, pyridine, pyrimidine, isoxazole, imidazole,oxazole, triazole, tetrazole, oxadiazole, thiazole, thiadiazole, andbenzoxazole. In another embodiment of this invention, heteroaryl istetrazole.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment of the present invention, halogen is selected from fluorine,chlorine, and bromine.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or ethyl acetate or a mixturethereof. The pair of enantiomers thus obtained may be separated intoindividual stereoisomers by conventional means, for example by the useof an optically active amine as a resolving agent or on a chiral HPLCcolumn.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. The term “pharmaceutically acceptable salt”further includes all acceptable salts such as acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, methylsulfate, camsylate,mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutamate, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine,succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of the present invention are activators of the AMP-activatedprotein kinase. The methods of treatment of this invention comprises amethod of activating AMPK-activated protein kinase and treatingAMPK-activated protein kinase mediated diseases by administering to apatient in need of such treatment a non-toxic therapeutically effectiveamount of a compound of this invention that activate AMPK-activatedprotein kinase.

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme composedof a catalytic α subunit and regulatory β and γ subunits. There are twogenes encoding isoforms of both the α and β subunits (α1, α2, β1 and β2)and three genes encoding isoforms of the γ subunit (γ1, γ2 and γ3)leading to 12 possible heterotrimeric combinations. The α2 isoform ispredominately found in skeletal and cardiac muscle AMPK; both the α1 andα2 isoforms are found in hepatic AMPK; while in pancreatic islet β-cellsthe α1 isoform AMPK predominates. In particular, the compounds ofstructural formula I are activators of at least one heterotrimericisoform of AMP-activated protein kinase.

An “activator” is a compound that either increases the activity(phosphorylation of downstream substrates) of fully phosphorylated AMPKor that increases the phosphorylation of AMPK.

The compounds of the present invention are efficacious in the treatmentand prevention of diseases, disorders and conditions responsive to theactivation of AMP-activated protein kinase, including but not limitedto: type 2 diabetes, insulin resistance, hyperglycemia, obesity,hyperinsulinemia, glucose intolerance, atherosclerosis, metabolicSyndrome, hypertension, high hepatic glucose output, high blood glucoseconcentrations, nonalcoholic steatohepatitis, protection againstischemia and reperfusion damage, and lipid disorders, such asdyslipidemia, elevated levels of plasma triglycerides, elevated levelsof free fatty acids, elevated levels of cholesterol, high levels of lowdensity lipoprotein (LDL) and low levels of high density lipoprotein(HDL). The compounds are also useful for the treatment of cancer,hypoxia and glucocorticoid-induced apoptosis.

One or more of the following diseases may be treated by theadministration of a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, to a patientin need of treatment: (1) non-insulin dependent diabetes mellitus (Type2 diabetes); (2) hyperglycemia; (3) metabolic syndrome; (4) obesity; (5)hypercholesterolemia; (6) hypertriglyceridemia (elevated levels oftriglyceride-rich-lipoproteins); (7) mixed or diabetic dyslipidemia; (8)low HDL cholesterol; (9) high LDL cholesterol; (10) atherosclerosis; and(11) hypertension.

Also, the compounds of Formula I may be used for the manufacture of amedicament for treating one or more of the above diseases.

One embodiment of the uses of the compounds is directed to the treatmentof one or more of the following diseases by administering atherapeutically effective amount to a patient in need of treatment: (1)Type 2 diabetes; (2) hyperglycemia; (3) metabolic syndrome; (4) obesity;(5) hypercholesterolemia; and (6) hypertension.

The compounds may also be used for manufacturing a medicament for use inthe treatment of one or more of the above diseases.

The compounds are expected to be effective in lowering glucose andlipids in diabetic patients and in non-diabetic patients who haveimpaired glucose tolerance and/or are in a pre-diabetic condition. Thecompounds may ameliorate hyperinsulinemia, which often occurs indiabetic or pre-diabetic patients, by modulating the swings in the levelof serum glucose that often occurs in these patients. The compounds mayalso be effective in treating or reducing insulin resistance. Thecompounds may be effective in treating or preventing gestationaldiabetes.

The compounds, compositions, methods and medicaments as described hereinmay also be effective in reducing the risks of adverse sequelaeassociated with metabolic syndrome, and in reducing the risk ofdeveloping atherosclerosis, delaying the onset of atherosclerosis,and/or reducing the risk of sequelae of atherosclerosis. Sequelae ofatherosclerosis include angina, claudication, heart attack, stroke, andothers. By keeping hyperglycemia under control, the compounds may alsobe effective in delaying or preventing vascular restenosis and diabeticretinopathy.

The compounds of this invention may also have utility in improving orrestoring β-cell function, so that they may be useful in treating type 1diabetes or in delaying or preventing a patient with Type 2 diabetesfrom needing insulin therapy.

Other possible outcomes of treatment with the compounds of the presentinvention include, but are not limited to: 1) a decrease in fatty acidsynthesis; 2) an increase in fatty acid oxidation and ketogenesis; 3) adecrease in cholesterol synthesis, lipogenesis, and triglyceridesynthesis; 4) a decrease in blood glucose levels and concentration; 5)an improvement in glucose homeostasis; 6) a normalization of glucosemetabolism; 7) a decrease in blood pressure; 8) an increase in HDL; 9) adecrease in plasma triglycerides; 10) a decrease in free fatty acids;11) a decrease in hepatic glucose output; 12) an improvement in insulinaction; 13) a decrease in blood pressure; 14) an improvement in insulinsensitivity; 15) a suppression of hepatic glucose output; 15) aninhibition of de novo lipogenesis; 16) stimulation of muscle glucoseuptake; 17) modulation of insulin secretion by pancreatic β cells; and16) a decrease in body weight.

The compounds generally may be efficacious in treating one or more ofthe following diseases: (1) Type 2 diabetes (also known as non-insulindependent diabetes mellitus, or NIDDM), (2) hyperglycemia, (3) impairedglucose tolerance, (4) insulin resistance, (5) obesity, (6) lipiddisorders, (7) dyslipidemia, (8) hyperlipidemia, (9)hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels,(12) high LDL levels, (13) atherosclerosis and its sequelae, (14)vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17)metabolic syndrome, (18) high blood pressure (hypertension), and (19)insulin resistance.

One aspect of the invention provides a method for the treatment andcontrol of mixed or diabetic dyslipidemia, hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/orhypertriglyceridemia, which comprises administering to a patient in needof such treatment a therapeutically effective amount of a compoundhaving formula I. The compound may be used alone or advantageously maybe administered with a cholesterol biosynthesis inhibitor, particularlyan HMG-CoA reductase inhibitor such as lovastatin, simvastatin,rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,itavastatin, or ZD-4522. The compound may also be used advantageously incombination with other lipid lowering drugs such as cholesterolabsorption inhibitors (for example stanol esters, sterol glycosides suchas tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (suchas avasimibe), CETP inhibitors (for example torcetrapib and thosedescribed in published applications WO2005/100298, WO2006/014413, andWO2006/014357), niacin and niacin receptor agonists, bile acidsequestrants, microsomal triglyceride transport inhibitors, and bileacid reuptake inhibitors. These combination treatments may be effectivefor the treatment or control of one or more related conditions selectedfrom the group consisting of hypercholesterolemia, atherosclerosis,hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and lowHDL.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of Type 2 diabetes by administeringthe compounds and pharmaceutical compositions of the present invention.The present invention also relates to methods and medicaments for thetreatment, control, or prevention of Type 2 diabetes by administeringthe compounds of the present invention in combination with atherapeutically effective amount of another agent known to be useful totreat the condition. The present invention also relates to methods andmedicaments for the treatment, control, or prevention of diabetesrelated disorders by administering the compounds and pharmaceuticalcompositions of the present invention alone, or in combination. Thepresent invention also relates to methods and medicaments for thetreatment and prevention of diabetes in pre-diabetic subject byadministering the compounds and pharmaceutical compositions of thepresent invention alone, or in combination.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of obesity by administering thecompounds and pharmaceutical compositions of the present invention. Thepresent invention also relates to methods and medicaments for thetreatment, control, or prevention of obesity by administering thecompounds of the present invention in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition. The present invention also relates to methods and medicamentsfor the treatment, control, or prevention of obesity related disordersby administering the compounds and pharmaceutical compositions of thepresent invention alone, or in combination. The present invention alsorelates to methods and medicaments for the treatment and prevention ofobesity in overweight subject by administering the compounds andpharmaceutical compositions of the present invention alone, or incombination. The compounds are also useful for the treatment of obesityrelated disorders, or eating disorders associated with excessive foodintake, and complications associated therewith, including leftventricular hypertrophy, as well as treating or preventing obesity inother mammalian species, including canines and felines.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of hyperglycemia by administering thecompounds and pharmaceutical compositions of the present invention. Thepresent invention also relates to methods and medicaments for thetreatment, control, or prevention of hyperglycemia by administering thecompounds of the present invention in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of insulin resistance by administeringthe compounds and pharmaceutical compositions of the present invention.The present invention also relates to methods and medicaments for thetreatment, control, or prevention of insulin resistance by administeringthe compounds of the present invention in combination with atherapeutically effective amount of another agent known to be useful totreat the condition.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of lipid disorders by administeringthe compounds and pharmaceutical compositions of the present invention.The present invention also relates to methods and medicaments for thetreatment, control, or prevention of lipid disorders by administeringthe compounds of the present invention in combination with atherapeutically effective amount of another agent known to be useful totreat the condition. The present invention also relates to methods andmedicaments for the treatment, control, or prevention of dyslipidemiarelated disorders and lipid disorder-related disorders by administeringthe compounds and pharmaceutical compositions of the present inventionalone, or in combination.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of atherosclerosis by administeringthe compounds and pharmaceutical compositions of the present invention.The present invention also relates to methods and medicaments for thetreatment, control, or prevention of atherosclerosis by administeringthe compounds of the present invention in combination with atherapeutically effective amount of another agent known to be useful totreat the condition. The present invention also relates to methods andmedicaments for the treatment, control, or prevention of atherosclerosisrelated disorders by administering the compounds and pharmaceuticalcompositions of the present invention alone, or in combination.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of hypertension by administering thecompounds and pharmaceutical compositions of the present invention. Thepresent invention also relates to methods and medicaments for thetreatment, control, or prevention of hypertension by administering thecompounds of the present invention in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition. The present invention also relates to methods and medicamentsfor the treatment, control, or prevention of hypertension relateddisorders by administering the compounds and pharmaceutical compositionsof the present invention alone, or in combination. The present inventionalso relates to methods and medicaments for the treatment and preventionof hypertension in pre-hypertensive subject by administering thecompounds and pharmaceutical compositions of the present inventionalone, or in combination.

The present invention also relates to methods and medicaments for thetreatment, control, or prevention of metabolic syndrome by administeringthe compounds and pharmaceutical compositions of the present invention.The present invention also relates to methods and medicaments fortreating metabolic syndrome by administering the compounds of thepresent invention in combination with a therapeutically effective amountof another agent known to be useful to treat the condition.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type 2 diabetics are also obese. The compositions of thepresent invention are useful for treating both Type 1 and Type 2diabetes. The term “diabetes associated with obesity” refers to diabetescaused by obesity or resulting from obesity. The compositions areespecially effective for treating Type 2 diabetes. The compositions ofthe present invention are also useful for treating and/or preventinggestational diabetes mellitus.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. A pre diabeticsubject is someone suffering from prediabetes. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of ≧140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat a diabeticsubject. One outcome of treatment may be decreasing the glucose level ina subject with elevated glucose levels. Another outcome of treatment maybe decreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensivity. Another outcome of treatmentmay be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to meandisorders that are associated with, caused by, or result from diabetes.Examples of diabetes related disorders include retinal damage, kidneydisease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of an anti-obesity agentin combination with a therapeutically effective amount of ananti-hypertensive agent may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists. Theterm “atherosclerosis related disorders” should be understood to meandisorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (≧140 mmHg/≧90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as less than 120 mmHg systolic and less than 80 mmHg diastolic.A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg. One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecompounds and combinations of the present invention to treathypertension in a hypertensive subject. Treatment ofhypertension-related disorder refers to the administration of a compoundor combination of the present invention to treat thehypertension-related disorder. Prevention of hypertension, or ahypertension related disorder, refers to the administration of thecombinations of the present invention to a pre-hypertensive subject toprevent the onset of hypertension or a hypertension related disorder.The hypertension-related disorders herein are associated with, causedby, or result from hypertension. Examples of hypertension-relateddisorders include, but are not limited to: heart disease, heart failure,heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolismincluding various conditions characterized by abnormal concentrations ofone or more lipids (i.e. cholesterol and triglycerides), and/orapolipoproteins (i.e., apolipoproteins A, B, C and E), and/orlipoproteins (i.e., the macromolecular complexes formed by the lipid andthe apolipoprotein that allow lipids to circulate in blood, such as LDL,VLDL and IDL). Hyperlipidemia is associated with abnormally high levelsof lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment ofdyslipidemia refers to the administration of the combinations of thepresent invention to a dyslipidemic subject. Prevention of dyslipidemiarefers to the administration of the combinations of the presentinvention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is asubject with higher than normal lipid levels, that is not yetdyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder relateddisorders” should be understood to mean disorders associated with,caused by, or resulting from dyslipidemia or lipid disorders. Examplesof dyslipidemia related disorder and lipid disorder related disordersinclude, but are not limited to: hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high density lipoprotein (HDL) levels, highplasma low density lipoprotein (LDL) levels, atherosclerosis and itssequelae, coronary artery or carotid artery disease, heart attack, andstroke.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². An overweightsubject is a subject at risk of obesity. A “subject at risk of obesity”is an otherwise healthy subject with a BMI of 25 kg/m² to less than 30kg/m² or a subject with at least one co-morbidity with a BMI of 25 kg/m²to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes mellitus, non-insulin dependent diabetesmellitus—type 2, diabetes associated with obesity, impaired glucosetolerance, impaired fasting glucose, insulin resistance syndrome,dyslipidemia, hypertension, hypertension associated with obesity,hyperuricacidemia, gout, coronary artery disease, myocardial infarction,angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fattyliver; cerebral infarction, cerebral thrombosis, transient ischemicattack, orthopedic disorders, arthritis deformans, lumbodynia,emmeniopathy, and infertility. In particular, co-morbidities include:hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,cardiovascular disease, sleep apnea, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, OH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The compounds of formula I are also useful for treating or preventingobesity and obesity-related disorders in cats and dogs. As such, theterm “mammal” includes companion animals such as cats and dogs.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III, or ATP III), National Institutesof Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA,vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined ashaving metabolic syndrome if the person has three or more of thefollowing disorders: abdominal obesity, hypertriglyceridemia, low HDLcholesterol, high blood pressure, and high fasting plasma glucose. Thecriteria for these are defined in ATP-III. Treatment of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with metabolic syndrome. Prevention of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with two of the disorders that define metabolicsyndrome. A subject with two of the disorders that define metabolicsyndrome is a subject that has developed two of the disorders thatdefine metabolic syndrome, but has not yet developed three or more ofthe disorders that define metabolic syndrome.

Left ventricular hypertrophy (LVH) is identified based on leftventricular mass index (LVMI) and relative wall thickness (RWT). Leftventricular mass index is defined as left ventricular mass in gramsdivided by body surface area in meters². Relative wall thickness isdefined as 2× posterior wall thickness/left ventricular end diastolicdiameter. Normal LVMI values are typically 85 and normal RWTapproximately 0.36. A male subject with LVH has a LVMI greater than 131g/m²; a female subject with LVH has a LVMI greater than 100 g/m². Asubject with an elevated LVMI value is a male subject with a LVMIbetween 85 g/m² and 131 g/m², or a female subject with a LVMI between 85g/m² and 100 g/m².

Treatment of cardiac hypertrophy, or left ventricular hypertrophy,refers to the administration of the combinations of the presentinvention to a subject with cardiac hypertrophy or left ventricularhypertrophy. Prevention of cardiac hypertrophy, or left ventricularhypertrophy, refers to the administration of the combinations of thepresent invention to decrease or maintain the LVMI in a subject with anelevated LVMI value or to prevent the increase of LVMI in a subject witha normal LVMI value.

One outcome of treatment of cardiac hypertrophy or left ventricularhypertrophy may be a decrease in ventricular mass. Another outcome oftreatment of cardiac hypertrophy or left ventricular hypertrophy may bea decrease in the rate of increase of ventricular mass. Another outcomeof treatment of cardiac hypertrophy or left ventricular hypertrophy maybe a decrease in ventricular wall thickness. Another outcome oftreatment of cardiac hypertrophy of left ventricular hypertrophy may bethe decrease in the rate of increase in ventricular wall thickness.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual or mammal in need oftreatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician or veterinarian in charge of the case, butdepends on factors such as the exact disease to be treated, the severityof the disease and other diseases or conditions from which the patientsuffers, the chosen route of administration other drugs and treatmentswhich the patient may concomitantly require, and other factors in thephysician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 100 mg in oneembodiment from about 0.01 mg to about 50 mg, and in another embodimentfrom 0.1 mg to 10 mg of a compound of Formula I per kg of body weightper day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1000 mg of a compound ofFormula I per day. In one embodiment, the range is from about 0.1 mg toabout 10 mg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing from 0.01 to 1,000mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 12.5, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, particularly a human or a companion animal such as a dog or cat,with an effective dosage of a compound of the present invention. Forexample, oral, rectal, topical, parenteral, ocular, pulmonary, and nasalroutes of administration, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. Thecompositions include compositions suitable for oral, rectal, topical,parenteral (including subcutaneous, intramuscular, and intravenous),ocular (ophthalmic), pulmonary (aerosol inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers, or as powders which may beformulated and the powder composition may be inhaled with the aid of aninsufflation powder inhaler device. The preferred delivery systems forinhalation are metered dose inhalation (MDI) aerosol, which may beformulated as a suspension or solution of a compound of Formula I insuitable propellants, such as fluorocarbons or hydrocarbons and drypowder inhalation (DPI) aerosol, which may be formulated as a dry powderof a compound of Formula I with or without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compounds of the presentinvention include those known to those of ordinary skill in that art.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, includingelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet cachet orcapsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05,0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50,75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated.

Additional suitable means of administration of the compounds of thepresent invention include injection, intravenous bolus or infusion,intraperitoneal, subcutaneous, intramuscular, intranasal, and topical,with or without occlusion.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Tablet mg/tablet Compound of FormulaI 10 Compound of Formula I 25 Methylcellulose 5.0 MicrocrystallineCellulose 415 Tween 80 0.5 Povidone 14.0 Benzyl alcohol 9.0Pregelatinized Starch 43.5 Benzalkonium chloride 1.0 Magnesium Stearate2.5 Water for injection to a total volume of 1 mL 500 Capsule mg/capsuleAerosol Per canister Compound of Formula I 25 Compound of Formula I 24mg Lactose Powder 573.5 Lecithin, NF Liq. Conc. 1.2 mg MagnesiumStearate 1.5 Trichlorofluoromethane, NF 4.025 g 600Dichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases, disorders or conditions for which compounds of Formula I areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of Formula I. When a compound of Formula I is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofFormula I is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients, in addition to a compound of Formula I. Examples ofother active ingredients that may be combined with a compound of FormulaI include, but are not limited to: other anti-diabetic agents,anti-dyslipidemic agents, and anti-hypertensive agents, anti-obesityagents, and anorectic agents, which may be administered separately or inthe same pharmaceutical compositions.

The present invention also provides a method for the treatment orprevention of an AMPK-activated protein kinase (AMPK) mediated disease,which method comprises administration to a patient in need of suchtreatment or at risk of developing an AMPK mediated disease of an amountof an AMPK activator and an amount of one or more active ingredients,such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising an AMPK activator and one or moreactive ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of an AMPK activator and one or more active ingredientsfor the manufacture of a medicament for the treatment or prevention ofan AMPK mediated disease. In a further or alternative aspect of thepresent invention, there is therefore provided a product comprising anAMPK activator and one or more active ingredients as a combinedpreparation for simultaneous, separate or sequential use in thetreatment or prevention of an AMPK mediated disease. Such a combinedpreparation may be, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of diabetes,obesity, hypertension, metabolic syndrome, dyslipidemia, cancer,atherosclerosis, and related disorders thereof, a compound of thepresent invention may be used in conjunction with another pharmaceuticalagent effective to treat that disorder.

The present invention also provides a method for the treatment orprevention of diabetes, obesity, hypertension, metabolic syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent effective to threat that disorder, suchthat together they give effective relief.

The present invention also provides a method for the treatment orprevention of diabetes, obesity, hypertension, metabolic syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, such that together they give effective relief.

Suitable pharmaceutical agents of use in combination with a compound ofthe present invention, include, but are not limited to:

(a) anti-diabetic agents such as (1) PPARγ agonists such as glitazones(e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555);pioglitazone (ACTOS); rosiglitazone (AVANDIA); troglitazone;rivoglitazone, BRL49653; CLX-0921; 5-BTZD, GW-0207, LG-100641, R483, andLY-300512, and the like and compounds disclosed in WO97/10813, 97/27857,97/28115, 97/28137, 97/27847, 03/000685, and 03/027112 and SPPARMS(selective PPAR gamma modulators) such as T131 (Amgen), FK614(Fujisawa), netoglitazone, and metaglidasen; (2) biguanides such asbuformin; metformin; and phenformin, and the like; (3) protein tyrosinephosphatase-1B (PTP-1B) inhibitors such as ISIS 113715, A-401674,A-364504, IDD-3, IDD 2846, KP-40046, KR61639, MC52445, MC52453, C7,OC-060062, OC-86839, OC29796, TTP-277BC1, and those agents disclosed inWO 04/041799, 04/050646, 02/26707, 02/26743, 04/092146, 03/048140,04/089918, 03/002569, 04/065387, 04/127570, and US 2004/167183; (4)sulfonylureas such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide, andthe like; (5) meglitinides such as repaglinide, metiglinide (GLUFAST)and nateglinide, and the like; (6) alpha glucoside hydrolase inhibitorssuch as acarbose; adiposine; camiglibose; emiglitate; miglitol;voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945;and MOR 14, and the like; (7) alpha-amylase inhibitors such astendamistat, trestatin, and Al-3688, and the like; (8) insulinsecreatagogues such as linogliride nateglinide, mitiglinide (GLUFAST),ID1101 A-4166, and the like; (9) fatty acid oxidation inhibitors, suchas clomoxir, and etomoxir, and the like; (10) A2 antagonists, such asmidaglizole; isaglidole; deriglidole; idazoxan; earoxan; and fluparoxan,and the like; (11) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (17-36),GLP-1 (73-7) (insulintropin); GLP-1 (7-36)-NH₂) exenatide/Exendin-4,Exenatide LAR, Linaglutide, AVE0010, CJC 1131, BIM51077, CS 872, TH0318,BAY-694326, GP010, ALBUGON (GLP-1 fused to albumin), HGX-007 (Epacagonist), S-23521, and compounds disclosed in WO 04/022004, WO 04/37859,and the like; (12) non-thiazolidinediones such as JT-501, andfarglitazar (GW-2570/GI-262579), and the like; (13) PPARα/γ dualagonists such as AVE 0847, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297,L-796449, LBM 642, LR-90, LY510919, MK-0767, ONO 5129, SB 219994,TAK-559, TAK-654, 677954 (GlaxoSmithkline), E-3030 (Eisai), LY510929(Lilly), AK109 (Asahi), DRF2655 (Dr. Reddy), DRF8351 (Dr. Reddy), MC3002(Maxocore), TY51501 (ToaEiyo), farglitazar, naveglitazar, muraglitazar,peliglitazar, tesaglitazar (GALIDA), reglitazar (JT-501), chiglitazar,and those disclosed in WO 99/16758, WO 99/19313, WO 99/20614, WO99/38850, WO 00/23415, WO 00/23417, WO 00/23445, WO 00/50414, WO01/00579, WO 01/79150, WO 02/062799, WO 03/033481, WO 03/033450, WO03/033453; and (14), insulin, insulin mimetics and other insulinsensitizing drugs; (15) VPAC2 receptor agonists; (16) GLK modulators,such as PSN105, RO 281675, RO 274375 and those disclosed in WO03/015774, WO 03/000262, WO 03/055482, WO 04/046139, WO 04/045614, WO04/063179, WO 04/063194, WO 04/050645, and the like; (17) retinoidmodulators such as those disclosed in WO 03/000249; (18) GSK 3beta/GSK 3inhibitors such as4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazol-5-yl]pyridine,CT21022, CT20026, CT-98023, SB-216763, SB410111, SB-675236, CP-70949,XD4241 and those compounds disclosed in WO 03/037869, 03/03877,03/037891, 03/024447, 05/000192, 05/019218 and the like; (19) glycogenphosphorylase (HGLPa) inhibitors, such as AVE 5688, PSN 357, GPi-879,those disclosed in WO 03/037864, WO 03/091213, WO 04/092158, WO05/013975, WO 05/013981, US 2004/0220229, and JP 2004-196702, and thelike; (20) ATP consumption promotors such as those disclosed in WO03/007990; (21) fixed combinations of PPAR γ agonists and metformin suchas AVANDAMET; (22) PPAR pan agonists such as GSK 677954; (23) GPR40(G-protein coupled receptor 40) also called SNORF 55 such as BG 700, andthose disclosed in WO 04/041266, 04/022551, 03/099793; (24) GPR119(G-protein coupled receptor 119, also called RUP3; SNORF 25) such asRUP3, HGPRBMY26, PFI 007, SNORF 25; (25) adenosine receptor 2Bantagonists such as ATL-618, ATI-802, E3080, and the like; (26)carnitine palmitoyl transferase inhibitors such as ST 1327, and ST 1326,and the like; (27) Fructose 1,6-bisphosphohatase inhibitors such asCS-917, MB7803, and the like; (28) glucagon antagonists such as AT77077,BAY 694326, GW 4123X, NN2501, and those disclosed in WO 03/064404, WO05/00781, US 2004/0209928, US 2004/029943, and the like; (30)glucose-6-phosphase inhibitors; (31) phosphoenolpyruvate carboxykinase(PEPCK) inhibitors; (32) pyruvate dehydrogenase kinase (PDK) activators;(33) RXR agonists such as MC1036, CS00018, JNJ 10166806, and thosedisclosed in WO 04/089916, U.S. Pat. No. 6,759,546, and the like; (34)SGLT inhibitors such as AVE 2268, KGT 1251, T1095/RWJ 394718; (35)BLX-1002; (36) alpha glucosidase inhibitors; (37) glucagon receptoragonists; (38) glucokinase activators; 39) GIP-1; and 40) insulinsecretagogues;

(b) anti-dyslipidemic agents such as (1) bile acid sequestrants such as,cholestyramine, colesevelam, colestipol, dialkylaminoalkyl derivativesof a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and thelike; (2) HMG-CoA reductase inhibitors such as atorvastatin,itavastatin, pitavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, simvastatin, rosuvastatin (ZD-4522), and other statins,particularly simvastatin; (3) HMG-CoA synthase inhibitors; (4)cholesterol absorption inhibitors such as FMVP4 (Forbes Medi-Tech),KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (Forbes Medi-Tech), FM-VP-24(Forbes Medi-Tech), stanol esters, beta-sitosterol, sterol glycosidessuch as tiqueside; and azetidinones such as ezetimibe, and thosedisclosed in WO 04/005247 and the like; (5) acyl coenzyme A-cholesterolacyl transferase (ACAT) inhibitors such as avasimibe, eflucimibe,pactimibe (KY505), SMP 797 (Sumitomo), SM32504 (Sumitomo), and thosedisclosed in WO 03/091216, and the like; (6) CETP inhibitors such as JTT705 (Japan Tobacco), torcetrapib, CP 532,632, BAY63-2149 (Bayer), SC591, SC 795, and the like; (7) squalene synthetase inhibitors; (8)anti-oxidants such as probucol, and the like; (9) PPARα agonists such asbeclofibrate, bezafibrate, ciprofibrate, clofibrate, etofibrate,fenofibrate, gemcabene, and gemfibrozil, GW 7647, BM 170744 (Kowa),LY518674 (Lilly), GW590735 (GlaxoSmithkline), KRP-101 (Kyorin), DRF10945(Dr. Reddy), NS-220/R1593 (Nippon Shinyaku/Roche, ST1929 (Sigma Tau)MC3001/MC3004 (MaxoCore Pharmaceuticals, gemcabene calcium, other fibricacid derivatives, such as Atromid®, Lopid® and Tricor®, and thosedisclosed in U.S. Pat. No. 6,548,538, and the like; (10) FXR receptormodulators such as GW 4064 (GlaxoSmithkline), SR 103912, QRX401, LN-6691(Lion Bioscience), and those disclosed in WO 02/064125, WO 04/045511,and the like; (11) LXR receptor modulators such as GW 3965(GlaxoSmithkline), T9013137, and XTCO179628 (X-CeptorTherapeutics/Sanyo), and those disclosed in WO 03/031408, WO 03/063796,WO 04/072041, and the like; (12) lipoprotein synthesis inhibitors suchas niacin; (13) renin angiotensin system inhibitors; (14) PPAR δ partialagonists, such as those disclosed in WO 03/024395; (15) bile acidreabsorption inhibitors, such as BARI 1453, SC435, PHA384640, S8921,AZD7706, and the like; and bile acid sequestrants such as colesevelam(WELCHOL/CHOLESTAGEL), colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran, (16) PPAR

agonists such as GW 501516 (Ligand, GSK), GW 590735, GW-0742(GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly), NNC610050 (NovoNordisk) and those disclosed in WO97/28149, WO 01/79197, WO 02/14291, WO02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO 03/033493, WO03/035603, WO 03/072100, WO 03/097607, WO 04/005253, WO 04/007439, andJP10237049, and the like; (17) triglyceride synthesis inhibitors; (18)microsomal triglyceride transport (MTTP) inhibitors, such asimplitapide, LAB687, JTT130 (Japan Tobacco), CP346086, and thosedisclosed in WO 03/072532, and the like; (19) transcription modulators;(20) squalene epoxidase inhibitors; (21) low density lipoprotein (LDL)receptor inducers; (22) platelet aggregation inhibitors; (23) 5-LO orFLAP inhibitors; and (24) niacin receptor agonists including HM74Areceptor agonists; (25) PPAR modulators such as those disclosed in WO01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/016265, WO03/033453; (26) niacin-bound chromium, as disclosed in WO 03/039535;(27) substituted acid derivatives disclosed in WO 03/040114; (28)infused HDL such as LUV/ETC-588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer),ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), synthetic trimericApoA1, Bioral Apo A1 targeted to foam cells, and the like; (29) IBATinhibitors such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis, PHA384640E(Pfizer), 58921 (Shionogi) AZD7806 (AstrZeneca), AK105 (Asah Kasei), andthe like; (30) Lp-PLA2 inhibitors such as SB480848 (GlaxoSmithkline),659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), and the like; (31)other agents which affect lipic composition including ETC1001/ESP31015(Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin),AZD4619 (AstrZeneca); and

(c) anti-hypertensive agents such as (1) diuretics, such as thiazides,including chlorthalidone, chlorthiazide, dichlorophenamide,hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics,such as bumetanide, ethacrynic acid, furosemide, and torsemide;potassium sparing agents, such as amiloride, and triamterene; andaldosterone antagonists, such as spironolactone, epirenone, and thelike; (2) beta-adrenergic blockers such as acebutolol, atenolol,betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol,celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol,penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, andtimolol, and the like; (3) calcium channel blockers such as amlodipine,aranidipine, azelnidipine, barnidipine, benidipine, bepridil,cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, and verapamil, and the like; (4)angiotensin converting enzyme (ACE) inhibitors such as benazepril;captopril; cilazapril; delapril; enalapril; fosinopril; imidapril;losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril;perindropril; quanipril; spirapril; tenocapril; trandolapril, andzofenopril, and the like; (5) neutral endopeptidase inhibitors such asomapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat, AVE7688,ER4030, and the like; (6) endothelin antagonists such as tezosentan,A308165, and YM62899, and the like; (7) vasodilators such ashydralazine, clonidine, minoxidil, and nicotinyl alcohol, nicotinic acidor salt thereof, and the like; (8) angiotensin II receptor antagonistssuch as candesartan, eprosartan, irbesartan, losartan, pratosartan,tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270,and the like; (9) α/

adrenergic blockers as nipradilol, arotinolol and amosulalol, and thelike; (10) alpha 1 blockers, such as terazosin, urapidil, prazosin,bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164, andXEN010, and the like; (11) alpha 2 agonists such as lofexidine,tiamenidine, moxonidine, rilmenidine and guanobenz, and the like; (12)aldosterone inhibitors, and the like; (13) angiopoietin-2-binding agentssuch as those disclosed in WO 03/030833; and

(d) anti-obesity agents, such as (1) 5HT (serotonin) transporterinhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, and imipramine, and those disclosed in WO 03/00663, as wellas serotonin/noradrenaline re uptake inhibitors such as sibutramine(MERIDIA/REDUCTIL) and dopamine uptake inhibitor/Norepenephrine uptakeinhibitors such as radafaxine hydrochloride, 353162 (GlaxoSmithkline),and the like; (2) NE (norepinephrine) transporter inhibitors, such as GW320659, despiramine, talsupram, and nomifensine; (3) CB1 (cannabinoid-1receptor) antagonist/inverse agonists, such as taranabant, rimonabant(ACCOMPLIA Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), AVE1625(Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326(Solvay), CP945598 (Pfizer), E-6776 (Esteve), O1691 (Organix), ORG14481(Organon), VER24343 (Vernalis), NESS0327 (Univ of Sassari/Univ ofCagliari), and those disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837,5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941, 6,028,084, and6,509367; and WO 96/33159, WO97/29079, WO98/31227, WO 98/33765,WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967,WO00/10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO03/007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, WO04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO05/000301, WO 05/016286, WO 05/066126 and EP-658546 and the like; (4)ghrelin agonists/antagonists, such as BVT81-97 (BioVitrum), RC1291(Rejuvenon), SRD-04677 (Sumitomo), unacylated ghrelin(TheraTechnologies), and those disclosed in WO 01/87335, WO 02/08250, WO05/012331, and the like; (5) H3 (histamine H3) antagonist/inverseagonists, such as thioperamide, 3-(1H-imidazol-4-yl)propylN-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan,GT2394 (Gliatech), and A331440, and those disclosed in WO 02/15905; andO-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)) and histamine H3 receptor modulators such as those disclosed inWO 03/024928 and WO 03/024929; (6) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda), T71(Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464(GlaxoSmithkline), A224940 (Abbott), A798 (Abbott), ATC0175/AR224349(Arena Pharmaceuticals), GW803430 (GlaxoSmithkline), NBI-1A (NeurocrineBiosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847(Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama MedicalSchool/University of California Irvine), and those disclosed WO01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO04/087680; and Japanese Patent Application Nos. JP 13226269, JP 1437059,JP2004315511, and the like; (7) MCH2R (melanin concentrating hormone 2R)agonist/antagonists; (8) NPY1 (neuropeptide Y Y1) antagonists, such asBMS205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, andGI-264879A; and those disclosed in U.S. Pat. No. 6,001,836; and WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5) antagonists,such as 152,804, S2367 (Shionogi), E-6999 (Esteve), GW-569180A,GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X; FR 235,208;FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, C-75(Fasgen) LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A,S2367(Shionogi), JCF-104, and H409/22; and those compounds disclosed in U.S.Pat. Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375,6,329,395, 6,335,345, 6,337,332, 6,329,395, and 6,340,683; andEP-01010691, EP-01044970, and FR252384; and PCT Publication Nos. WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO02/094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO05/014592, WO 05/01493; and Norman et al., J. Med. Chem. 43:4288-4312(2000); (10) leptin, such as recombinant human leptin (PEG-OB, HoffmanLa Roche) and recombinant methionyl human leptin (Amgen); (11) leptinderivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524;5,552,523; 5,552,522; 5,521,283; and WO 96/23513; WO 96/23514; WO96/23515; WO 96/23516; WO 96/23517; WO 96/23518; WO 96/23519; and WO96/23520; (12) opioid antagonists, such as nalmefene (Revex®),3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed in WO00/21509; (13) orexin antagonists, such as SB-334867-A(GlaxoSmithkline); and those disclosed in WO 01/96302, 01/68609,02/44172, 02/51232, 02/51838, 02/089800, 02/090355, 03/023561,03/032991, 03/037847, 04/004733, 04/026866, 04/041791, 04/085403, andthe like; (14) BRS3 (bombesin receptor subtype 3) agonists; (15) CCK-A(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180,A-71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide,and those disclosed in U.S. Pat. No. 5,739,106; (16) CNTF (ciliaryneurotrophic factors), such as GI-181771 (Glaxo-SmithKline); SR146131(Sanofi Synthelabo); butabindide; and PD170,292, PD 149164 (Pfizer);(17) CNTF derivatives, such as axokine (Regeneron); and those disclosedin WO 94/09134, WO 98/22128, and WO 99/43813; (18) GHS (growth hormonesecretagogue receptor) agonists, such as NN703, hexarelin, MK-0677,SM-130686, CP-424,391, L-692,429 and L-163,255, and those disclosed inU.S. Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and2002/022637; and WO 01/56592, and WO 02/32888; (19) 5HT2c (serotoninreceptor 2c) agonists, such as APD3546/AR10A (Arena Pharmaceuticals),ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK),DPCA37215 (BMS), IK264; LY448100 (Lilly), PNU 22394; WAY 470 (Wyeth),WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche)YM 348; and those disclosed in U.S. Pat. No. 3,914,250; and PCTPublications 01/66548, 02/36596, 02/48124, 02/10169, 02/44152; 02/51844,02/40456, 02/40457, 03/057698, 05/000849, and the like; (20) Mc3r(melanocortin 3 receptor) agonists; (21) Mc4r (melanocortin 4 receptor)agonists, such as CHIR86036 (Chiron), CHIR915 (Chiron); ME-10142(Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (NeurocrineBiosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech) and thosedisclosed in PCT Publications WO 99/64002, 00/74679, 01/991752,01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842,02/059095, 02/059107, 02/059108, 02/059117, 02/062766, 02/069095,02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388,02/067869, 02/081430, 03/06604, 03/007949, 03/009847, 03/009850,03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610,04/075823, 04/083208, 04/089951, 05/000339, and EP 1460069, and US2005049269, and JP2005042839, and the like; (22) monoamine reuptakeinhibitors, such as sibutratmine (Meridia®/Reductil®) and salts thereof,and those compounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570,and 5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO01/27068, and WO 01/62341; (23) serotonin reuptake inhibitors, such asdexfenfluramine, fluoxetine, and those in U.S. Pat. No. 6,365,633, andWO 01/27060, and WO 01/162341; (24) GLP-1 (glucagon-like peptide 1)agonists; (25) Topiramate (Topimax®); (26) phytopharm compound 57 (CP644,673); (27) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (28) β3 (betaadrenergic receptor 3) agonists, such as rafebergron/AD9677/TAK677(Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (GlenmarkPharmaceuticals) GW 427353 (solabegron hydrochloride), Trecadrine,Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), KT07924(Kissei), SR 59119A, and those disclosed in U.S. Pat. No. 5,705,515,U.S. Pat. No. 5,451,677; and WO94/18161, WO95/29159, WO97/46556,WO98/04526 WO98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO04/108674, and the like; (29) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (30) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(31) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75;(32) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, aminone, milrinone, cilostamide,rolipram, and cilomilast, as well as those described in WO 03/037432, WO03/037899; (33) thyroid hormone p agonists, such as KB-2611(KaroBioBMS), and those disclosed in WO 02/15845; and Japanese PatentApplication No. JP 2000256190; (34) UCP-1 (uncoupling protein 1), 2, or3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123;(35) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa,M. et al., Obesity Research, 9:202-9 (2001); (36) glucocorticoidreceptor antagonists, such as CP472555 (Pfizer), KB 3305, and thosedisclosed in WO 04/000869, WO 04/075864, and the like; (37) 11β HSD-1(11-beta hydroxy steroid dehydrogenase type 1) inhibitors, such as BVT3498 (AMG 331), BVT 2733,3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole,3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene,and those compounds disclosed in WO 01/90091, 01/90090, 01/90092,02/072084, 04/011410, 04/033427, 04/041264, 04/027047, 04/056744,04/065351, 04/089415, 04/037251, and the like; (38) SCD-1 (stearoyl-CoAdesaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DPP-4)inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,sitagliptin (Januvia), saxagliptin, alogliptin, NVP-DPP728, LAF237(vildagliptin), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364,VIP 0177, SDZ 274-444, GSK 823093, E 3024, SYR 322, TS021, SSR 162369,GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149, PT-630, SK-0403;and the compounds disclosed in WO 02/083128, WO 02/062764, WO 02/14271,WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/005766, WO03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/0214870, WO04/041273, WO 04/041820, WO 04/050658, WO 04/046106, WO 04/067509, WO04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO05/023762, US 2005/043292, and EP 1 258 476; (40) lipase inhibitors,such as tetrahydrolipstatin (orlistat/XENICAL), ATL962 (Alizyme/Takeda),GT389255 (Genzyme/Peptimmune) Triton WR1339, RHC80267, lipstatin,teasaponin, and diethylumbelliferyl phosphate, FL-386, WAY-121898,Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, and RHC80267, and those disclosed in WO 01/77094, WO 04/111004, and U.S. Pat.Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644,4,189,438, and 4,242,453, and the like; (41) fatty acid transporterinhibitors; (42) dicarboxylate transporter inhibitors; (43) glucosetransporter inhibitors; and (44) phosphate transporter inhibitors; (45)anorectic bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis),and the compounds disclosed in WO 00/18749, WO 01/32638, WO 01/62746, WO01/62747, and WO 03/015769; (46) peptide YY and PYY agonists such asPYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin),TM30335/TM30338 (7™ Pharma), PYY336 (Emisphere Technologies), pegylatedpeptide YY3-36, those disclosed in WO 03/026591, 04/089279, and thelike; (47) lipid metabolism modulators such as maslinic acid,erythrodiol, ursolic acid uvaol, betulinic acid, betulin, and the likeand compounds disclosed in WO 03/011267; (48) transcription factormodulators such as those disclosed in WO 03/026576; (49) Mc5r(melanocortin 5 receptor) modulators, such as those disclosed in WO97/19952, WO 00/15826, WO 00/15790, US 20030092041, and the like; (50)Brain derived neurotropic factor (BDNF), (51) Mc1r (melanocortin 1receptor modulators such as LK-184 (Proctor & Gamble), and the like;(52) 5HT6 antagonists such as BVT74316 (BioVitrum), BVT5182c(BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885(GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche), andthe like; (53) fatty acid transport protein 4 (FATP4); (54) acetyl-CoAcarboxylase (ACC) inhibitors such as CP640186, CP610431, CP640188(Pfizer); (55) C-terminal growth hormone fragments such as AOD9604(Monash Univ/Metabolic Pharmaceuticals), and the like; (56)oxyntomodulin; (57) neuropeptide FF receptor antagonists such as thosedisclosed in WO 04/083218, and the like; (58) amylin agonists such asSymlin/pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulonextracts; (60) BVT74713 and other gut lipid appetite suppressants; (61)dopamine agonists such as bupropion (WELLBUTRIN/GlaxoSmithkline); (62)zonisamide (ZONEGRAN/Dainippon/Elan), and the like; and

(e) anorectic agents suitable for use in combination with a compound ofthe present invention include, but are not limited to, a minorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof. A particularly suitable classof anorectic agent are the halogenated amphetamine derivatives,including chlorphentermine, cloforex, clortermine, dexfenfluramine,fenfluramine, picilorex and sibutramine; and pharmaceutically acceptablesalts thereof. Particular halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, and losartan, losartan withhydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO03/077847, including:N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,and pharmaceutically acceptable salts thereof; as well as those inWO05/000809, which includes the following:3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile,1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol.3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,and5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile,and pharmaceutically acceptable salts thereof; as well as:3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile,and pharmaceutically acceptable salts thereof.

Specific NPY5 antagonists of use in combination with a compound of thepresent invention include:3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,and pharmaceutically acceptable salts and esters thereof.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof.

Specific MCH1R antagonist compounds of use in combination with acompound of the present invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific H3 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905, including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{-4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof.

Specific MC4R agonists of use in combination with a compound of thepresent invention include: 1)(5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile;and pharmaceutically acceptable salts thereof.

Suitable neurokinin-1 (NK-1) receptor antagonists may be favorablyemployed with the AMP-kinase activators of the present invention. NK-1receptor antagonists of use in the present invention are fully describedin the art. Specific neurokinin-1 receptor antagonists of use in thepresent invention include:(±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763; or a pharmaceuticallyacceptable salts thereof.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a DPIVinhibitor the weight ratio of the compound of the Formula Ito the DPIVinhibitor will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of theFormula I and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes,Intermediates and Examples, using appropriate materials and are furtherexemplified by the following specific examples. Moreover, by utilizingthe procedures described in the disclosure contained herein, one ofordinary skill in the art can readily prepare additional compounds ofthe present invention claimed herein. The compounds illustrated in theexamples are not, however, to be construed as forming the only genusthat is considered as the invention. The Examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. The instant compounds aregenerally isolated in the form of their pharmaceutically acceptablesalts, such as those previously described herein. The use of protectinggroups for the amine and carboxylic acid functionalities to facilitatethe desired reaction and minimize undesired reactions is welldocumented. Conditions required to remove protecting groups are found instandard textbooks such as Greene, T, and Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y.,1991. CBZ and BOC are commonly used protecting groups in organicsynthesis, and their removal conditions are known to those skilled inthe art. All temperatures are degrees Celsius unless otherwise noted.Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.

Abbreviations used in the description of the preparation of thecompounds of the present invention: aq is aqueous; ACN is acetonitrile;AcOH is acetic acid; Bn is benzyl; BnBr is benzyl bromide; C is carbon;cone is concentrated; d is day(s); DAST is (diethylamino)sulfurtrifluoride; DIBAL-His di-isobutyl aluminum hydride; DCM isdichloromethane; DME is 1,2-dimethoxyethane; DMF is dimethyl formamide;DMSO is dimethyl sulfoxide; dppf is1,1′-bis(diphenylphosphino)-ferrocene; Et is ethyl; EtO is ethoxy; Et₂Ois diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et₃N istriethyl amine; Et₃Si is triethyl silane; eq is equivalent; g isgram(s); h is hour(s); HMDS is hexamethyldisilizane; HPLC is highpressure liquid chromatography; i-Pr is isopropyl; O-i-Pr is isopropoxy;KOAc is potassium acetate; L is liter; LC/MS is liquidchromatography/mass spectroscopy; LDA is lithium diisopropyl amide; M ismolar; ml or mL is milliliter; Me is methyl; MeCN is acetonitrile; MeIis methyl iodide; MeO is methoxy; MeOH is methanol; min is minutes; mmis millimeters of mercury; mmol is millimole(s); MP or Mp or mp ismelting point; MPLC is medium pressure liquid chromatography; N isnormal; NaOAc is sodium acetate; NBS is N-bromo succinamide; NIS isN-iodo succinamide; PPh₃ is triphenyl phosphine; wt % is weight percent;psi is pounds per square inch; RT or r.t. or rt is room temperature; Rtis retention time; Rochelles' Salt is potassium sodium tartrate; SEM is2-(trimethylsilyl)-ethoxymethyl; SEMCl is2-(trimethylsilyl)-ethoxymethyl chloride; Bu₄NF and TBAF is tetrabutylammonium fluoride; TBS is tert-butyl dimethyl silyl chloride; TBSCl istert-butyl dimethyl silyl chloride; TFA is trifluoro acetic acid; THF istetrahydrofuran; TLC is thin layer chromatography; TMS istetramethylsilyl; and TMSBr is tetramethylsilyl bromide.

Microwave (MW or mw) reactions were performed with a single modeoperating Biotage Emrys Optimizer in sealed reaction vials at theindicated fixed temperature held constant for the designated reactiontime. The medium pressure liquid chromatography (MPLC) purificationswere performed with Teledyne ISCO RediSep normal-phase columnspre-packed with 35-60 micron silica gel. The LC-MS system contained anApplied Biosystems API150EX MS operating in a positive ion modereceiving 0.1 mL/min flowrate with a Shimadzu UV detector receiving 0.1mL/min flowrate. Unless specified, the LC conditions were solventA=0.03% TFA in acetonitrile; solvent B=0.05% TFA in water; flowrate=10mL/min; column: Chromolith Performance RP-18e, 100×4.6 mm; gradientprogram: min (% B) 0 (95), 1.6 (5), 2.6 (5), 2.7 (95), 3.0 (95). Unlessspecified, the ¹H NMRs were obtained in DMSO-d₆ at 300 or 500 MHz andspectra were recorded in units δ with CD₂HS(O)CD₃ (δ 2.504) as thereference line internal standard. C, H, N microanalyses were performedby Robertson Microlit Laboratories, Inc., Madison, N.J.

The following reaction schemes illustrate methods which may be employedfor the synthesis of the compounds of structural formula I described inthis invention. All substituents are as defined above unless indicatedotherwise. Several strategies based upon synthetic transformations knownin the literature of organic synthesis may be employed for thepreparation of the title compounds of general formula I.

Intermediate 1

5-chloro-4-iodo-2-nitroaniline

To a solution of 5-chloro-2-nitroaniline (25 g, 145 mmol) in AcOH (250mL) was added N-iodosuccinimide (32.6 g 145 mmol). The mixture wasstirred overnight at 50° C., cooled to rt and filtered. The solidresidue was washed with AcOH, water, saturated aqueous NaHCO₃ and water,and then dried to afford the desired product as a brown solid, which wasused in the next step without further purification.

Intermediate 2

5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione Step A4-chloro-5-iodobenzene-1,2-diamine

To a suspension of 5-chloro-4-iodo-2-nitroaniline (Intermediate 1, 36.5g, 122 mmol) in EtOH (800 mL) and water (150 mL) was added iron powder(38 g, 673 mmol) and NH₄Cl (16 g, 306 mmol). The mixture was heatedunder nitrogen at 50° C. overnight. Additional iron powder (38 g, 673mmol) and NH₄Cl (16 g, 306 mmol) were added and heating was continuedfor 45 h. The reaction mixture was cooled, filtered and concentrated.The residue was re-dissolved in ethyl acetate and washed with sodiumbicarbonate solution. The organic phase was concentrated to afford thedesired product as a gray solid, which was used in the next step withoutfurther purification.

Step B 5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione

KOH (15.7 g, 238 mmol) in water (50 mL), followed by carbon disulfide(14.4 mL, 238 mmol), was added to a solution of4-chloro-5-iodobenzene-1,2-diamine (50 g, 198 mmol) in EtOH (300 mL).The mixture was heated at reflux for 3 h, cooled and filtered. To thefiltrate was added water (300 mL) and then AcOH (25 mL) in water (50mL). The precipitate was collected, washed with water and a small amountof EtOH and dried to afford the desired product as a brown powder, whichwas used in the next step without further purification.

Intermediate 3

6-chloro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole Step A6-chloro-5-iodo-2-(methylthio)-1H-benzimidazole

K₂CO₃ (0.22 g, 1.61 mmol), followed by iodomethane (0.1 mL, 1.61 mmol),was added to a solution of5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione (Intermediate 2, 1g, 3.22 mmol) in acetone (20 mL) at 0° C. The reaction was stirred at rtfor 1 h. Additional K₂CO₃ (1.61 mmol) and iodomethane (1.61 mmol) wereadded, and stirring continued at rt overnight. Volatiles were removedand the residue was partitioned between EtOAc and water. Concentrationafforded the desired product as a white foam, which was used in the nextstep without further purification.

Step B 6-chloro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole

m-Chloroperbenzoic acid (1.4 g, 6.16 mmol) was added to a suspension of6-chloro-5-iodo-2-(methylthio)-1H-benzimidazole (1.0 g, 3.08 mmol) inDCM (50 mL). The reaction stirred at rt for 10 min then washed with 10%aqueous NaHCO₃. The organic phase was concentrated. The residue wastriturated with MeOH (3 mL) and filtered to afford the title compound aswhite powder. LC-MS: calculated for C₈H₆ClIN₂O₂S 356.57, observed m/e357.30 (M+H)⁺ (R_(t) 1.21/2 min). NMR (CD₃OD): 8.3 (1H, s), 7.9 (1H, s),3.3 (3H, s).

Intermediate 4

Tert-butyl 2-(6-chloro-5-iodo-1H-benzo[d]imidazol-2-ylthio)acetate

Cs₂CO₃ (2.3 g, 7.08 mmol), followed by text-butyl bromoacetate (0.52 mL,3.54 mmol), was added to a solution of5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione (Intermediate 2,1.1 g, 3.54 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rtfor 0.5 h. Volatiles were removed and the residue was partitionedbetween EtOAc and water. Concentration afforded the desired product as awhite power. LC-MS: calculated for C₁₃H₁₄ClIN₂O₂S 423.95, observed m/e424.8 (M+H)⁺.

Intermediate 5

6-chloro-5-iodo-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole

Et₃N (20.95 mL, 150 mmol) and 2-(trimethylsilyl)ethoxy methyl chloride(17.29 mL, 98 mmol) were added to a solution of Intermediate 3 (26.8 g,75 mmol) in THF (200 mL). The reaction was stirred at rt for 1 h.Volatiles were removed and the residue partitioned between EtOAc andwater. The organic phase was washed with 2N aqueous HCl and brine, dried(MgSO₄) and concentrated to afford the title compound as a white solid.LC-MS: calculated for C₁₄H₂₀ClN₂O₃SSi 485.97, observed m/e 428.83 (M+H)⁺(R_(t) 2.30 min).

Intermediate 6

4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol Step A4′-bromobiphenyl-2-ol

Potassium phosphate (2 M in water) (5.5 ml, 10.9 mmol) and Pd(PPh₃)₄(209 mg, 0.18 mmol) were added to a solution of 1-bromo-4-iodobenzene(2.05 g, 7.25 mmol), and 2-hydroxybenzeneboronic acid (1 g, 7.25 mmol)in dioxane (50 mL). The reaction was heated at 100° C. for 1 h.Volatiles were removed and the residue was purified by chromatographyover silica eluting with 0-50% EtOAc/hexane to afford the desiredproduct as a light yellow oil.

Step B 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol

Potassium acetate (366 mg, 3.73 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium II DCM adduct(25.4 mg, 31 μmol) were added to a solution of 4′-bromobiphenyl-2-ol(310 mg, 1.24 mmol), and bis(pinacolato)diboron (348 mg, 1.37 mmol) inDME (3 mL). The reaction was heated at 150° C. under microwaveirradiation for 10 min. Reaction mixture was filtered through a pad ofCelite™ and purified by chromatography over silica eluting with 0-50%EtOAc/hexane to furnish the title compound as a white solid.

Intermediate 7

Methyl 2-(6-chloro-5-iodo-1H-benzo[d]imidazol-2-ylthio)acetate

A mixture of 6-chloro-5-iodo-2-thio-1H-benzo[d]imidazole (Intermediate2; 4.00 g, 12.9 mmol), methyl bromoacetate (1.2 mL, 12.9 mmol), andCs₂CO₃ (8.41 g, 25.8 mmol) in 65 mL of THF was stirred for 2.5 h at rt.The volume of the solvent was reduced by rotary evaporation to about 20mL, the mixture was diluted with 200 mL of EtOAc and washed with brine,dried (MgSO₄) and evaporated. The resulting residue was subjected tochromatography on an 80 g column of SiO₂ eluting with 14% EtOAc inhexanes, followed by 20% to provide the title compound as an amorphoussolid, which exists as a tautomer mixture in DMSO according to ¹H NMR:¹H NMR (500 MHz, DMSO-d₆): δ 3.66, 3.72, 3.73 (s each, 3H), 4.24, 4.25,4.26 (s each, 2H), 7.71, 7.95 (s each, 1H), 7.99, 8.11, 8.22 (s each,1H), 12.91 (br s, 1H); LC-MS: calculated for C₁₀H₈ClIN₂O₂S 382.6,observed m/e 382.9/384.9 (M+H)⁺.

Intermediate 8

(6-Chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl esterwas prepared according to the procedure described for Intermediate 7.

Intermediate 9

3-(5-bromo-6-chloro-1H-benzimidazol-2-yl)-propionic acid methyl estermay be prepared from the 5-bromo-6-chloro-phenyldiamine according to theprocedure disclosed in Synthesis of new trifluoromethyl-substituted11H-isoindolo[2,1-a]benzimidazol-11-one derivatives, Lingaiah,Boddupally P. V.; Yakaiah, Tallapally; Rao, Pamulaparthy S.; andNarsaiah, Banda, Heterocycles (2005), 65(10), 2329-2337.

In General Scheme 1, Intermediate 1 is reacted with a boronic acid,boronate ester or stannane (R¹-M) in the presence of palladium catalystto afford compound 1A. Alternatively, Intermediate 1 is reacted with anacetylene (R¹—H) in the presence of palladium catalyst to affordcompound 1A. The subsequent reduction of 1A with iron powder/ammoniumchloride affords benzyldiamine 1B. Treatment of compound 1B with carbondisulfide under basic conditions gives1,3-dihydro-2H-benzimidazole-2-thione 1C. The subsequent reaction withbromoacetic acid affords the final 2-substituted benzimidazole product.

Example 1(6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-ylsulfanyl)-acetic acid

Step A 5-Chloro-2-nitro-4-phenylethynyl-phenylamine (1-1)

A 20 mL scintillation vial equipped with a stirring bar and a septum capwas charged with Pd(OAc)₂ (5.6 mg, 5 mol %) and5-chloro-4-iodo-2-nitro-phenylamine (Intermediate 1, 149.0 mg, 0.500mmol). The vial was purged with N₂ and a solution of ethynyl-benzene(56.1 mg, 0.549 mmol) was added followed by a solution oftetrabutylammonium acetate (182.0 mg, 0.750 mmol) in DMF (3 mL). Theresulting mixture was stirred at 65° C. for 18 h, cooled down to rt,diluted with water (4 mL) and extracted with EtOAc (3 mL, then twicewith 1 mL). The organic layers were combined, washed with water (threetimes, 1 mL) and evaporated to dryness in vacuo. The resulting residuewas dissolved in 1:1 MeOH/EtOAc (3 mL) and passed through a ThiolStratoSphere™ SPE cartridge (Polymer Labs). The solution was evaporatedto dryness in vacuo to give the crude product as brown solid. LR-MS(API-ES): calculated for C₁₄H₉ClN₂O₂ 272.1, observed m/e 273.0 (M+H)⁺(R_(t) 3.40 min). The crude product was used in the next step withoutfurther purification.

Step B. 4-Chloro-5-phenylethynyl-benzene-1,2-diamine (1-2)

A 2 mL Biotage™ microwave vial was charged with Fe (67.0 mg, 1.19 mmol),a solution of compound 1-1 (65.0 mg, 0.238 mmol) in EtOH (2 mL) and anaqueous solution of NH₄Cl (6.38 mg, 0.119 mmol in 0.5 mL of water). Theresulting suspension was heated in a microwave synthesizer (BiotageInitiator™) at 140° C. for 10 min. The mixture was then filtered and theremaining solids were washed with EtOAc (three times, 2 mL). Thefiltrate and washes were combined and evaporated to dryness in vacuo togive the crude product as brown solid. LR-MS (API-ES): calculated forC₁₄H₁₁ClN₂ 242.1, observed m/e 243.0 (M+H)⁺ (R_(t) 2.91 min). The crudeproduct was used in the next step without further purification.

Step C. 5-Chloro-6-phenylethynyl-1,3-dihydro-benzoimidazole-2-thione(1-3)

A 2 mL Biotage™ microwave vial was charged with solid KOH (19.4 mg,0.345 mmol), water (0.2 mL), a solution of compound 1-2 (55.8 mg, 0.230mmol) in EtOH (1.2 mL) and carbon disulfide (69 uL, 1.2 mmol). The vialwas capped and stirred at rt until KOH dissolved, and then heated in amicrowave synthesizer (Biotage Initiator™) at 110° C. for 10 min.Contents of the vial were transferred to a 20 mL scintillation vial,diluted with water (8 mL) and acidified by the dropwise addition of 10%aqueous AcOH. The resulting suspension was centrifuged, the supernatantwas decanted and the resulting brownish precipitate was washed with 10%aqueous AcOH (3 mL) and water (three times 3 mL). The precipitate wasdissolved in EtOAc and passed through a short plug of neutral alumina.The EtOAc solution was evaporated to dryness in vacuo to give the crudeproduct as brownish solid. LR-MS (API-ES): calculated for C₁₅H₉ClN₂S284.0, observed m/e 285.0 (M+H)⁺. (R_(t) 2.94 min). The crude productwas used in the next step without further purification.

Step D. (6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-ylsulfanyl)-aceticacid (1-4)

A solution of bromoacetic acid (47.8 mg, 0.344 mmol) in EtOH (1 mL) wasadded dropwise to a 20 mL scintillation vial equipped with a stirringbar and a septum cap containing a solution of compound 1-3 (49.0 mg,0.172 mmol) in EtOH (1 mL). To this solution, 1M KOH (2 mL) was addeddropwise, and the resulting mixture was stirred at rt for 1 h. Thereaction mixture was then diluted with water (4 mL) and acidified with10% aqueous HCl. The solution was extracted with EtOAc (3 mL then twice1 mL), extracts were combined and evaporated to dryness in vacuo. Theresulting oily residue was dissolved in DMSO (1.0 mL), filtered andpurified by reverse-phase HPLC to give the title compound as whitesolid. LR-MS (API-ES): calculated for C₁₇H₁₁ClN₂O₂S 342.0, observed m/e343.1 (M+H)⁺ (R_(t) 7.71 min).

Example 2(5-Biphenyl-4-yl-6-chloro-1H-benzoimidazol-2-ylsulfanyl)-acetic acid

Step A. 2-Chloro-5-nitro-[1,1′;4′,1″]terphenyl-4-ylamine (2-1)

A 5 mL Biotage™ microwave vial was charged with FibreCat™ (Aldrich, 0.4mmol/g; 37.5 mg, 3 mol %) and biphenyl-4-boronic acid (119.0 mg, 0.600mmol). A solution of 5-chloro-4-iodo-2-nitro-phenylamine (Intermediate1, 149.0 mg, 0.500 mmol) in EtOH (4.4 mL) was added followed by 1Maqueous K₂CO₃ (0.6 mL). The vial was heated in a microwave synthesizer(Biotage Initiator™) at 110° C. for 8 min. Contents of the vial werediluted with EtOAc (2 mL) and filtered. The resulting precipitate waswashed with EtOAc (three times, 2 mL). The filtrate and washes werecombined and evaporated to dryness in vacuo. The residue was dissolvedin EtOAc (4 mL), washed with 1M aqueous K₂CO₃ (twice, 1 mL) andevaporated to dryness in vacuo to give an orange-yellow solid. LR-MS(API-ES): calculated for C₁₈H₁₃ClN₂O₂ 324.1, observed m/e 367.2 (100%),347.0 ((M+Na)⁺, 325.0 (M+H)⁺, (R_(t) 3.56 min). The crude product wasused in the next step without further purification.

Step B. 6-Chloro-[1,1′;4′,1″]terphenyl-3,4-diamine (2-2)

A 5 mL Biotage™ microwave vial was charged with Fe (285.0 mg, 5.11mmol), a solution of compound 2-1 (166.0 mg, 0.511 mmol) in EtOH (3 mL)and diluted aqueous HCl (82 uL of 37% aqueous HCl, diluted with 0.75 mLof water). The resulting suspension was heated in a microwavesynthesizer (Biotage Initiator™) at 130° C. for 10 min. The mixture wasthen filtered and the remaining solids were washed with EtOAc (threetimes, 2 mL). The filtrate and washes were combined and evaporated todryness in vacuo. The residue was dissolved in 3:1 EtOAc/TEA and passedthrough a short plug of a neutral alumina. The resulting solution wasevaporated to dryness in vacuo to give the crude product as brownishoil. LR-MS (API-ES): calculated for C₁₈H₁₅ClN₂ 294.1, observed m/e 295.0(M+H)⁺ (R_(t) 3.07 min). The crude product was used in the next stepwithout further purification.

Step C. 5-Biphenyl-4-yl-6-chloro-1,3-dihydro-benzoimidazole-2-thione(2-3)

A 2 mL Biotage™ microwave was charged with solid KOH (18.0 mg, 0.326mmol), water (0.2 mL), a solution of compound 2-2 (64.0 mg, 0.217 mmol)in EtOH (1.2 mL) and carbon disulfide (65 uL, 1.1 mmol). The vial wascapped and stirred at rt until KOH dissolved then heated in a microwavesynthesizer (Biotage Initiator™) at 110° C. for 10 min. Contents of thevial were transferred to a 20 mL scintillation vial, diluted with water(6 mL) and acidified by a dropwise addition of 10% aqueous AcOH. Theresulting suspension was centrifuged, the supernatant was decanted andthe resulting brownish precipitate was washed with 10% aqueous AcOH (3mL) and water (three times, 3 mL). The precipitate was then dissolved inEtOAc and passed through a short plug of neutral alumina. The EtOAcsolution was evaporated to dryness in vacuo to give the crude product asyellow solid. LR-MS (API-ES): calculated for C₁₉H₁₃ClN₂S 336.1, observedm/e 337.0 (M+H)⁺ (R_(t) 3.12 min). The crude product was used in thenext step without further purification.

Step D. (5-Biphenyl-4-yl-6-chloro-1H-benzoimidazol-2-ylsulfanyl)-aceticacid (2-4)

A solution of bromoacetic acid (43.4 mg, 0.312 mmol) in EtOH (1 mL) wasadded dropwise to a 20 mL scintillation vial equipped with a stirringbar and a septum cap containing a solution of compound 2-3 (52.6 mg,0.156 mmol) in EtOH (0.5 mL). To this solution, 1M KOH (1.5 mL) wasadded dropwise, and the resulting mixture was stirred at rt for 1 h. Thereaction mixture was then diluted with water (4 mL) and acidified with10% aqueous HCl. The solution was extracted with EtOAc (3 mL, then threetimes 1 mL). Extracts were combined and evaporated to dryness in vacuo.The resulting oily residue was dissolved in DMSO (1 mL), filtered andpurified by reverse-phase HPLC with to give the title compound as whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.70-7.76 (4H, m), 7.64 (1H, s),7.46-7.55 (4H, m), 7.45 (1H, s), 7.36-7.40 (1H, m), 4.12 (2H, s); LRMS(API-ES): calculated for C₂₁H₁₅ClN₂O₂S 394.1, observed m/e 395.0 (M+H)⁺(R_(t) 3.14 min).

TABLE 1 Examples 3-5 in Table 1 were prepared following the proceduresdescribed in Example 2 and Scheme 1 by substituting biphenyl-4-boronicacid with the appropriate boronic acid or ester. Example Formula/ LCMSNo Name Structure Calculated (M + H)+ 3 (5-1,3-benzo- dioxol-5-yl-6-chloro-1H- benzimidazol- 2-ylsulfanyl)- acetic acid

C₁₆H₁₁ClN₂O₄S 362.01 362.9 4 [6-chloro-5- (3-fluoro- phenyl)-1H-benzimidazol- 2-ylsulfanyl]- acetic acid

C₁₅H₁₀ClFN₂O₂S 336.01 336.9 5 [6-chloro-5- (3,5-difluoro- phenyl)-1H-benzimidazol- 2-ylsulfanyl]- acetic acid

C₁₅H₉ClF₂N₂O₂S 354.00 355.0

In General Scheme 2, Intermediate 4 is reacted with a boronic acid,boronate ester or stannane (R¹-M) in the presence of palladiumtetrakistriphenylphosphine to afford compound 2A. Alternatively,Intermediate 4 is reacted with an acetylene (R¹—H) in the presence ofcopper (I) iodide and bis(triphenylphosphine)palladium (II) chloride toafford compound 2A. Subsequent hydrolysis of compound 2A under acidic orbasic conditions affords the 2-substituted benzimidazole 2B.

Example 62-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)aceticacid

Step A tert-butyl2-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)acetate

A solution of potassium carbonate (1 M solution in water, 0.15 mL, 0.15mmol), Pd(PPh₃)₄ (3 mg, 0.0002 mmol),4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol (15 mg,0.05 mmol) and Intermediate 4 (21 mg, 0.05 mmol) in dioxane (0.25 mL)was heated at 80° C. for 15 h. The aqueous phase was removed and theorganic phase was concentrated, diluted with EtOAc, filtered andconcentrated to afford the desired product as a solid, which was used inthe next step without further purification.

Step B2-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)aceticacid

A solution of tert-butyl2-(6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-benzo[d]imidazol-2-ylthio)acetatein TFA (0.9 mL) and water (0.1 mL) was stirred at room temperature for 2h and concentrated. The resultant solid was purified with HPLC to affordthe desired product. LCMS: calculated for C₂₁H₁₅ClN₂O₃S 410.05, observedm/e 411.0 (M+H)⁺.

TABLE 2 Examples 7-17 in Table 2 were prepared following the proceduresdescribed in Example 6 and General Scheme 2 by substituting theappropriate boronic acid, boronate ester, stannane or acetylene from theIntermediates, or from commercial sources; and followed by subsequentester hydrolysis. HPLC- mass Example. spectrum No. Name Structure m/e 72-(6-(4-(acetamido- methyl)phenyl)-5- chloro-1H-benzo[d]-imidazol-2-ylthio)- acetic acid

390 8 2-(6-chloro-5-(4- hydroxyphenyl)-1H- benzo[d]imidazol-2-ylthio)acetic acid

335 9 2-(6-chloro-5-(4- (hydroxymethyl)phenyl)- 1H-benzo[d]-imidazol-2-ylthio)- acetic acid

349 10 2-(5-((2-amino- phenyl)ethynyl)-6- chloro-1H-benzo[d]-imidazol-2-ylthio)- acetic acid

11 2-(6-chloro-5-(1H- indazol-6-yl)-1H- benzo[d]imidazol-2-ylthio)acetic acid

359 12 2-(6-chloro-5-(6- methoxypyridin-3-yl)- 1H-benzo[d]imidazol-2-ylthio)acetic acid

350 13 2-(5-(benzofuran-2- yl)-6-chloro-1H- benzo[d]imidazol-2-ylthio)acetic acid

359 14 2-(5-(benzo[b]- thiophen-3-yl)-6- chloro-1H-benzo[d]-imidazol-2-ylthio)- acetic acid

375 15 2-(5-(4-(1H-pyrazol- 1-yl)phenyl)-6-chloro- 1H-benzo[d]imidazol-2-ylthio)acetic acid

385 16 2-(5-(4-(1H-pyrazol- 5-yl)phenyl)-6-chloro- 1H-benzo[d]imidazol-2-ylthio)acetic acid

385 17 2-(5-((3-acetamido- phenyl)ethynyl)-6- chloro-1H-benzo[d]-imidazol-2-ylthio)- acetic acid

400

Example 18[6-Chloro-5-(4-hydroxymethyl-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]-aceticacid

Step A.[6-Chloro-5-(4-hydroxymethyl-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]-aceticacid tert-butyl ester (18-1)

A 2 mL Biotage™ microwave vial was charged with copper iodide (1.1 mg,10 mol %), and Pd(PPh₃)₂Cl₂ (2.1 mg, 5 mol %). A solution of(6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butylester (Intermediate 4, 25.0 mg, 0.059 mmol) in DMF (0.5 mL) was added tothe vial, followed by a solution of (4-ethynyl-phenyl)-methanol (15.0mg, 0.118 mmol) in DMF (250 uL) and TEA (57 uL, 0.41 mmol). Theresulting suspension was heated in a microwave synthesizer (BiotageInitiator™) at 120° C. for 5 min. The solvent was removed in vacuo togive dark brown oil which was used in the next step without furtherpurification. LR-MS (API-ES): calculated for C₂₂H₂₁ClN₂O₃S 428.1,observed m/e 429.0 (M+H)⁺ (R_(t) 3.05 min).

Step B.[6-Chloro-5-(4-hydroxymethyl-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]-aceticacid (18-2)

In a 4 mL vial, compound 18-1 (25.3 mg, 0.059 mmol) was dissolved in 9:1TFA/water (2 mL) and stirred at rt for 2 h. The solution was evaporatedto dryness in vacuo to give oily brown residue, which was dissolved inDMSO (1.25 mL), filtered and purified by reverse-phase HPLC to give thetitle compound. LR-MS (API-ES): calculated for C₁₈H₁₃ClN₂O₃S 372.0,observed m/e 372.9 (M+H)⁺ (R_(t) 1.87 min).

TABLE 3 Examples 19-32 in Table 3 were prepared following the proceduresdescribed in Example 18 and Scheme 2A by substituting(4-ethynyl-phenyl)-methanol with the appropriate terminal acetylene.Example Formula/ LCMS No Name Structure Calculated (M + H)+ 19[6-chloro-5-(4- methanesulfonyl- phenyl-ethynyl)- 1H-benzo-imidazol-2-yl- sulfanyl]-acetic acid

C₁₈H₁₃ClN₂O₄S₂ 420.00 420.9 20 [6-chloro-5-(2- cyano-phenyl-ethynyl)-1H- benzo-imidazol- 2-ylsulfanyl]- acetic acid

C₁₈H₁₀ClN₃O₂S 367.02 368.0 21 (6-chloro-5- piperidin-4- ylethynyl-1H-benzoimidazol-2- ylsulfanyl)-acetic acid

C₁₆H₁₆ClN₃O₂S 349.07 350.0 22 6-chloro-5-(4- fluoro-phenyl- ethynyl)-1H-benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₇H₁₀ClFN₂O₂S 360.01 360.9 23 6-chloro-5-(3- fluoro-phenyl-ethynyl)-1H- benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₇H₁₀ClFN₂O₂S 360.01 360.9 24 [6-chloro-5-(2,4- difluoro-phenyl-ethynyl)-1H- benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₇H₉ClF₂N₂O₂S 378.00 378.9 25 (6-chloro-5- pyridin-4-yl- ethynyl-1H-benzoimidazol-2- ylsulfanyl)-acetic acid

C₁₆H₁₀ClN₃O₂S 343.02 344.0 26 [6-chloro-5-(3- phenoxy-prop-1-ynyl)-1H-benzo- imidazol-2-yl- sulfanyl]-acetic acid

C₁₈H₁₃ClN₂O₃S 372.03 372.9 27 6-chloro-5-(2- fluoro-phenyl- ethynyl)-1H-benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₇H₁₀ClFN₂O₂S 360.01 360.9 28 [6-chloro-5-(4- cyano-phenyl-elhynyl)-1H- benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₈H₁₀ClN₃O₂S 367.02 368.0 29 [6-chloro-5-(3- hydroxyphenyl-ethynyl)-1H- benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₇H₁₁ClN₂O₃S 358.02 359.0 30 (6-chloro-5-o- tolylethynyl-1H-benzo-imidazol- 2-ylsulfanyl)- acetic acid

C₁₈H₁₃ClN₂O₂S 356.04 357.0 31 (6-chloro-5-m- tolylethynyl-1H-benzoimidazol-2- ylsulfanyl)-acetic acid

C₁₈H₁₃ClN₂O₂S 356.04 357.0 32 [6-chloro-5-(3- methoxy-phenyl-ethynyl)-1H- benzoimidazol-2- ylsulfanyl]-acetic acid

C₁₈H₁₃ClN₂O₃S 372.03 372.9

Example 33[6-Chloro-5-(4-phenoxy-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]-aceticacid

Step A.[6-Chloro-5-(4-phenoxy-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]-aceticacid tert-butyl ester (33-1)

A 2 mL Biotage™ microwave vial equipped with a stirring bar was chargedwith copper iodide (1.1 mg, 10 mol %), and Pd(PPh₃)₂Cl₂ (2.1 mg, 5 mol%). A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-aceticacid tert-butyl ester (Intermediate 4, 25.0 mg, 0.059 mmol) in DMF (0.5mL) was added to the vial, followed by a solution of1-ethynyl-4-phenoxy-benzene (15.0 mg, 0.118 mmol) in DMF (250 uL) andTEA (57 uL, 0.41 mmol). The resulting suspension was heated in amicrowave synthesizer (Biotage Initiator™) at 120° C. for 5 min. Thesolvent was removed in vacuo to give dark brown oil which wasre-dissolved in a 1:1 MeOH/EtOAc mixture (3 mL) and passed through aThiol StratoSphere™ SPE cartridge (Polymer Labs). The resulting solutionwas evaporated to dryness in vacuo to give the crude product as brownsolid. LR-MS (API-ES): calculated for C₂₇H₂₃ClN₂O₃S 490.1, observed m/e491.0 (M+H)⁺ (R_(t) 3.74 min). The crude product was used in the nextstep without further purification.

Step B.[6-Chloro-5-(4-phenoxy-phenylethynyl)-1H-benzoimidazol-2-ylsulfanyl]aceticacid (33-2)

A solution of compound 33-1 (29.0 mg, 0.059 mmol) in MeOH (6 mL) wasadded to 5% aqueous LiOH (3 mL) and the mixture was stirred at rt for 20h. The mixture was then diluted with water (2 mL), evaporated to ½ ofthe initial volume and acidified with 5% aqueous HCl. The solution wasextracted with EtOAc (3 mL then 1 mL, twice). The organic layers werecombined, washed with water (three times, 1 mL) and evaporated todryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0mL), filtered and purified by reverse-phase HPLC to give the titlecompound as off-white solid. LR-MS (API-ES): calculated forC₂₃H₁₅ClN₂O₃S 434.1, observed m/e 435.0 (M+H)⁺ (R_(t) 2.96 min).

TABLE 4 Examples 34-39 in Table 4 were prepared following the proceduresdescribed in Example 33 and Scheme 2B by substituting1-ethynyl-4-phenoxy-benzene with the appropriate terminal acetylene.Example Formula/ LCMS No. Name Structure Calculated (M + H)+ 34(5-biphenyl-4- ylethynyl-6-chloro- 1H-benzoimidazol-2-ylsulfanyl)-acetic acid

C₂₃H₁₅ClN₂O₂S 418.05 419 35 (6-chloro-5-cyclo- pentylethynyl-1H-benzo-imidazol-2- yl-sulfanyl)-acetic acid

C₁₆H₁₅ClN₂O₂S 334.05 335 36 [6-chloro-5-(4- ethyl-phenyl-ethynyl)-1H-benzo- imidazol-2-yl- sulfanyl]-acetic acid

C₁₉H₁₅ClN₂O₂S 370.05 371 37 [6-chloro-5-(6- methoxy- naphthalen-2-yl-ethynyl)-1H-benzo- imidazol-2-yl- sulfanyl]-acetic acid

C₂₂H₁₅ClN₂O₃S 422.05 423 38 (6-chloro-5- thiophen-2-yl-ethynyl-1H-benzo- imidazol-2-yl- sulfanyl)-acetic acid

C₁₅H₉ClN₂O₂S₂ 347.98   348.9 39 [6-chloro-5-(4- methoxy-phenyl-ethynyl)-1H- benzimidazol-2- ylsulfanyl]-acetic acid

C₁₈H₁₃ClN₂O₃S 372.03   372.9

Example 40[5-(4-Benzyloxy-3-fluoro-phenyl)-6-chloro-1H-benzimidazol-2-ylsulfanyl]-aceticacid

Step A.[5-(4-Benzyloxy-3-fluoro-phenyl)-6-chloro-1H-benzimidazol-2-ylsulfanyl]-aceticacid tert-butyl ester (40-1)

A 4 mL vial with a septum cap and a stirring bar was charged with4-benzyloxy-3-fluoro-phenylboronic acid (14.8 mg, 0.060 mmol) andPd(PPh₃)₄ (5.8 mg, 5 mol %) and was purged briefly with N₂. A solutionof (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acidtert-butyl ester (Intermediate 4, 21.4 mg, 0.050 mmol) in toluene (200uL) was added to the vial, followed by a solution K₂CO₃ (21.4 mg, 0.050mmol) in water (100 uL). The resulting mixture was stirred at 80° C. for14 h. The mixture was allowed to cool down to rt, and was partitionedwith EtOAc (1 mL) and 10% aqueous AcOH (1 mL). The organic layer wasseparated evaporated to dryness in vacuo. LR-MS (API-ES) of the residueconfirmed the presence of the title compound: calculated forC₂₆H₂₄ClFN₂O₃S 498.1, observed m/e 499.0 (M+H)⁺ (R_(t) 3.54 min). Thecrude product was used in the next step without further purification.

Step B.[5-(4-Benzyloxy-3-fluoro-phenyl)-6-chloro-1H-benzimidazol-2-ylsulfanyl]-aceticacid (40-2)

In a 4 mL vial, a solution of compound 40-1 (25.0 mg, 0.050 mmol) in 8:1TFA/water (1 mL) was stirred at rt for 1 h. The mixture was then dilutedwith water (0.5 mL) and evaporated to dryness in vacuo. The resultingoily residue was dissolved in DMSO (1.0 mL), filtered and purified byreverse-phase HPLC to the title compound as a white solid. LR-MS(API-ES): calculated for C₂₂H₁₆ClFN₂O₃S 442.1, observed m/e 443.0 (M+H)⁺(R_(t) 3.10 min).

TABLE 5 Examples 41-44 in Table 5 were prepared following the proceduresdescribed in Example 40 and Scheme 2C by substituting4-benzyloxy-3-fluoro-phenylboronic acid with the appropriate boronicacid or ester. Example Formula/ LCMS No. Name Structure Calculated (M +H)+ 41 [6-chloro-5- (4-chloro- phenyl)-1H- benzimidazol- 2-ylsulfanyl]-acetic acid

C₁₅H₁₀C₁₂N₂O₂S 351.98 353.0 42 [6-chloro-5- (4-methoxy- phenyl)-1H-benzimidazol- 2-ylsulfanyl]- acetic acid

C₁₆H₁₃ClN₂O₃S 348.03 349.0 43 [6-chloro-5- (4-isobutyl- phenyl)-1H-benzimidazol- 2-ylsulfanyl]- acetic acid

C₁₉H₁₉ClN₂O₂S 374.09 375.0 44 [5-(4-benzyl- oxy-phenyl)- 6-chloro-1H-benzimidazol- 2-ylsulfanyl]- acetic acid

C₂₂H₁₇ClN₂O₃S 424.06 425.0

In General Scheme 3, Intermediate 5 is reacted with a boronic acid,boronate ester or stannane (R¹-M) in the presence of palladiumtetrakistriphenylphosphine to afford compound 3A. Alternatively,Intermediate 5 is reacted with an acetylene (R¹—H) in the presence ofcopper (I) iodide and bis(triphenylphosphine)palladium (II) chloride toafford compound 3A. Subsequent reaction of compound 3A with an alcoholand hydrolysis of the product 3B affords the 2-substituted benzimidazole3C.

Example 45{6-Chloro-5-[4-(2H-pyrazol-3-yl)-phenyl]-1H-benzoimidazol-2-yloxy}-aceticacid

Step A.6-Chloro-2-methanesulfonyl-5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(45-1)

A 5 mL Biotage™ microwave vial was charged with6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(Intermediate 5, 73.2 mg, 0.150 mmol), 4-(2H-pyrazol-3-yl)-phenylboronicacid (33.9 mg, 0.180 mmol) and Pd(PPh₃)₄ (8.7 mg, 5 mol %) followed bydioxane (1.5 mL) and 1M aqueous K₂CO₃ (180 uL). The resulting suspensionwas heated in a microwave synthesizer (Biotage Initiator™) at 130° C.for 10 min. The suspension was then diluted with EtOAc (5 mL) and washedwith 1M aqueous K₂CO₃ (twice, 1 mL) and water (twice, 1 mL). The organiclayer was evaporated to dryness in vacuo to give yellow oil. The oil wasdissolved in ACN and passed through a Thiol StratoSphere™ SPE cartridge(Polymer Labs). The solvent was evaporated to dryness in vacuo to givethe crude product as pale yellow solid. LR-MS (API-ES): calculated forC₂₃H₂₇ClN₄O₃SSi 502.1, observed m/e 503.0 (M+H)⁺ (R_(t) 3.30 min).

Step B.[5-[4-(2H-Pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (45-2)

A 20 mL scintillation vial equipped with a septum cap and a magneticstirring bar was charged under N₂ with NaH (18.0 mg, 60% suspension inmineral oil, 0.45 mmol). A solution of hydroxyacetic acid methyl ester(81.0 mg, 0.90 mmol) in THF (1.5 mL) was added dropwise to the vial.Immediately after the addition was complete, a solution of6-chloro-2-methanesulfonyl-5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(compound 45-1, 75.0 mg, 0.150 mmol) in THF (1 mL) was added. Theresulting suspension was stirred at rt for 5 min, then diluted with ACN(2 mL) and quenched by slow addition of water (2 mL). The resultingsolution was stirred at rt for 5 min, and then additional 15 min at 65°C. The solution was acidified with 5% aqueous HCl and extracted withEtOAc (three times, 3 mL). The organic layers were combined and washedwith 5% aqueous HCl and water and evaporated to dryness in vacuo to givethe title compound as yellowish oil. LR-MS (API-ES): mixture of twoN-SEM isomers, calculated for C₂₄H₂₇ClN₄O₄Si 498.2, observed m/e 499.0(M+H)⁺ (R_(t) 3.01, 3.15 min). The compound was used in the next stepwithout further purification.

Step C.{6-Chloro-5-[4-(2H-pyrazol-3-yl)-phenyl]-1H-benzoimidazol-2-yloxy}-aceticacid (45-3)

In a 4 mL vial,[5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (compound 45-2, 74.8 mg, 0.15 mmol) was dissolved in 9:1 TFA/water(1 mL). The solution was agitated at 65° C. for 15 min and evaporated todryness in vacuo to give yellowish oil. The oil was dissolved in DMSO (1mL), filtered and purified by reverse-phase HPLC to give the titlecompound as white solid. LR-MS (API-ES): calculated for C₁₈H₁₃ClN₄O₃368.1, observed m/e 369.0 (M+H)⁺ (R_(t) 2.31 min).

Example 46 [(5-biphenyl-4-yl-6-chloro-1H-benzimidazol-2-yl)oxy]ylaceticacid

Step A.5-Biphenyl-4-yl-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(46-1)

A 2 mL Biotage™ microwave vial was charged with6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(Intermediate 5, 49.0 mg, 0.100 mmol), biphenyl-4-boronic acid (24.0 mg,0.120 mmol) and Pd(PPh₃)₄ (5.8 mg, 5 mol %) following by dioxane (1.0mL) and 1M aqueous K₂CO₃ (120 uL). The resulting suspension was heatedin a microwave synthesizer (Biotage Initiator™) at 150° C. for 10 min.The microwave procedure was repeated two more times, before eachirradiation additional Pd(PPh₃)₄ (2.9 mg, 2.5 mol %) was added. Thereaction mixture was then diluted with EtOAc (5 mL), filtered and theresulting solution was evaporated to dryness in vacuo to give brown oil.The oil was dissolved in ACN and passed through a Thiol StratoSphere™SPE cartridge (Polymer Labs). The solvent was evaporated to dryness invacuo to give crude product as colorless oil which was used in the nextstep without further purification. LR-MS (API-ES): calculatedC₂₆H₂₉ClN₂O₃SSi 512.1, observed m/e 513.0 (M+H)⁺, 485.0, 455.0 (R_(t)3.91 min).

Step B.[5-Biphenyl-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (46-2)

A 20 mL scintillation vial equipped with a septum cap and a magneticstirring bar was charged under N₂ with NaH (6.0 mg, 60% suspension inmineral oil, 0.15 mmol). A solution of hydroxyacetic acid methyl ester(18.0 mg, 0.200 mmol) in THF (2.0 mL) was added dropwise to the vial andthe resulting mixture was stirred at rt for 10 min. Then, a solution of5-biphenyl-4-yl-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(compound 46-1, 51.3 mg, 0.100 mmol) in THF (1 mL) was added. Theresulting mixture was stirred at rt for 10 mM, then diluted by dropwiseaddition of 1:1 ACN/water (2 mL) and left to stir at rt for 30 min. Thereaction mixture was then diluted with water (5 mL), acidified with 5%aqueous HCl and extracted with EtOAc (three times, 3 mL). The organiclayers were combined and washed with 5% aqueous HCl and water, andevaporated to dryness in vacuo to give the title compound as pale yellowsolid. LR-MS (API-ES): mixture of two N-SEM isomers, calculated forC₂₇H₂₉ClN₂O₄Si 508.2, observed m/e 509.0 [(M+H)⁺, 100%], 465 (R_(t) 3.74min). The compound was used in the next step without furtherpurification.

Step C. [(5-biphenyl-4-yl-6-chloro-1H-benzimidazol-2-yl)oxy]acetic acid(46-3)

In a 4 mL vial,[5-biphenyl-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid methyl ester (compound 46-2, 52.3 mg, 0.100 mmol) was dissolved in9:1 TFA/water (3 mL). The solution was stirred at 65° C. for 10 min,then evaporated to dryness in vacuo to give pale yellow solid. The solidwas dissolved in DMSO (1 mL), filtered and purified by reverse-phaseHPLC to give the title compound as yellowish solid. LR-MS (API-ES):calculated for C₂₁H₁₅ClN₂O₃ 378.1, observed m/e 379.1 (M+H)⁺ (R_(t) 1.36min).

Example 47[5-(4-Hydroxymethyl-phenylethynyl)-1H-benzoimidazol-2-yloxy]-acetic acid

Step A.{4-[2-Methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-ylethynyl]-phenyl}-methanol(47-1)

A 4 mL vial equipped with a stirring bar was charged with copper iodide(1.0 mg, 5 mol %) and Pd(PPh₃)₂Cl₂ (2.0 mg, 2.5 mol %). A solution of6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(Intermediate 5, 49.0 mg, 0.100 mmol) in ACN (1 mL) was added to thevial, followed by a solution of (4-ethynyl-phenyl)-methanol (26.0 mg,0.200 mmol) in ACN (0.5 mL) and TEA (98 uL, 0.70 mmol). The resultingsuspension was stirred at it for 10 min, during which time it graduallyturned dark brown. The reaction mixture was than passed through a ThiolStratoSphere™ SPE cartridge (Polymer Labs). The resulting solution wasevaporated to dryness in vacuo to give yellow oil. The oil wasre-dissolved in ACN and passed through a short pad of silica.Evaporation of solvent provided the crude product as yellow oily solidwhich was used in the next step without further purification. LR-MS(API-ES): mixture of two N-SEM isomers, calculated C₂₃H₂₇ClN₂O₄SSi490.1, observed m/e 491.0 (M+H)⁺, 463.0, 433 (R_(t) 3.25, 3.40 min).

Step B.[5-(4-Hydroxymethyl-phenylethynyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (47-2)

A 20 mL scintillation vial equipped with a septum cap and a magneticstirring bar was charged under N₂ with NaH (12.0 mg, 60% suspension inmineral oil, 0.30 mmol). A solution of hydroxyacetic acid methyl ester(54.0 mg, 0.60 mmol) in THF (1.0 mL) was added dropwise to the vial.Immediately after the addition was complete, a solution of{4-[2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-ylethynyl]-phenyl}-methanol(compound 47-1, 49.1 mg, 0.100 mmol) in THF (1 mL) was added. Theresulting yellowish suspension was stirred at it for 5 min, then dilutedwith ACN (2 mL) and quenched by addition of water (2 mL). The resultingsolution was stirred at it for 5 min, then an additional 15 min at 65°C. The solution was acidified with 5% aqueous HCl and extracted withEtOAc (three times, 3 mL). The organic layers were combined and washedwith 5% aqueous HCl and water and evaporated to dryness in vacuo to givethe crude product as yellowish solid. LR-MS (APT-ES): mixture of twoN-SEM isomers, calculated for C₂₄H₂₇ClN₂O₅Si 486.2, observed m/e 487.0(M+H)⁺ (R_(t) 3.09, 3.20 min). The crude product was used in the nextstep without further purification.

Step C.[5-(4-Hydroxymethyl-phenylethynyl)-1H-benzoimidazol-2-yloxy]-acetic acid(47-3)

In a 4 mL vial,[5-(4-hydroxymethyl-phenylethynyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (compound 47-2, 48.7 mg, 0.100 mmol) was dissolved in 9:1 TFA/water(1 mL). The solution was stirred at rt for 45 min, then evaporated todryness in vacuo to give brownish oil. The oil was dissolved in DMSO (1mL), filtered and purified by reverse-phase HPLC to give the formatesalt of the title compound as a yellowish solid. LR-MS (API-ES):calculated for C₁₈H₁₃ClN₂O₄ 356.1, observed m/e 357.0 (M+H)⁺ (R_(t) 1.84min).

Example 48 (6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-yloxy)-aceticacid

Step A.6-Chloro-2-methanesulfonyl-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(48-1)

A 4 mL vial equipped with a stirring bar was charged with copper iodide(2.0 mg, 10 mol %), and Pd(PPh₃)₂Cl₂ (3.5 mg, 5 mol %). A solution of6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(Intermediate 5, 49.0 mg, 0.100 mmol) in DMF (0.5 mL) was added to thevial, followed by a solution of ethynyl-benzene (20.0 mg, 0.200 mmol) inDMF (0.5 mL) and TEA (98 uL, 0.70 mmol). The resulting suspension wasstirred at rt for 10 min, during which time it gradually turned brown.The solvent was then removed in vacuo to give brown oily solid, whichwas suspended in 1:1 EtOAc/MeOH (3 mL) and passed through a ThiolStratoSphere™ SPE cartridge (Polymer Labs). The resulting solution wasevaporated to dryness in vacuo to give light yellow oil. LR-MS (API-ES):calculated C₂₂H₂₅ClN₂O₃SSi 460.1, m/e (M+H)⁺ not observed, 433.0, 403(R_(t) 3.83 min).

Step B.[6-Chloro-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (48-2)

A 20 mL scintillation vial equipped with a septum cap and a magneticstirring bar was charged under N₂ with NaH (10.5 mg, 60% suspension inmineral oil, 0.26 mmol). A solution of hydroxyacetic acid methyl ester(54.0 mg, 0.35 mmol) in THF (2.0 mL) was added dropwise to the vial.Immediately after the addition was complete, a solution of[6-chloro-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (compound 48-1, 80.0 mg, 0.173 mmol) in THF (1 mL) was added. Theresulting yellowish suspension was stirred at rt for 10 min, thendiluted by a dropwise addition of 1:1 ACN/water (2 mL). The resultingsolution was stirred at rt for 1 h, and then evaporated to dryness invacuo to give the crude product as brown oil. LR-MS (API-ES): mixture oftwo N-SEM isomers, calculated for C₂₃H₂₅ClN₂O₄Si 456.1, observed m/e457.0 (M+H)⁺ (R_(t) 3.09, 3.20 min). The crude product was used in thenext step without further purification.

Step C. (6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-yloxy)-acetic acid(48-3)

In a 4 mL vial,[6-chloro-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-aceticacid (compound 48-2, 79.0 mg, 0.173 mmol) was dissolved in 9:1 TFA/water(3 mL) and stirred at 65° C. for 10 min. The solution was thenevaporated to dryness in vacuo to give brownish oil, which was dissolvedin DMSO (1 mL), filtered and purified by reverse-phase HPLC to give thetitle compound as a yellowish solid. LR-MS (API-ES): calculated forC₁₇H₁₁ClN₂O₃ 326.1, observed m/e 327.1 (M+H)⁺ (R_(t) 1.25 min).

In General Scheme 4, Intermediate 3 is reacted with a boronic acid,boronate ester or stannane (R¹-M) in the presence of palladiumtetrakistriphenylphosphine to afford compound 4A. Alternatively,Intermediate 3 is reacted with an acetylene (R¹—H) in the presence ofcopper (I) iodide and bis(triphenylphosphine)palladium (II) chloride toafford compound 4A. Subsequent protection with SEM-Cl followed byreaction of SEM protected reaction intermediate 4B with an alcohol, thenhydrolysis of the product 4C affords the 2-substituted benzimidazole 4D.

Example 493-(6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-yloxy)-2,2-dimethyl-propionicacid

Step A.6-Chloro-2-methanesulfonyl-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(49-1)

A 2 mL Biotage™ microwave vial was charged with copper iodide (5.7 mg,10 mol %), and Pd(PPh₃)₂Cl₂ (10.5 mg, 5 mol %). A solution of6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (Intermediate 3,107.0 mg, 0.300 mmol) in DMF (0.75 mL) was added to the vial, followedby a solution of ethynyl-benzene (61.0 mg, 0.600 mmol) in DMF (0.5 mL)and TEA (293 uL, 2.10 mmol). The resulting suspension was heated in amicrowave synthesizer (Biotage Initiator™) at 110° C. for 5 min. Thesolvent was then removed in vacuo to give dark brown oil, which wassuspended in 1:1 EtOAc/MeOH (3 mL), passed through a Thiol StratoSphere™SPE cartridge (Polymer Labs). The resulting solution was evaporated todryness in vacuo to give the crude product as a brown solid. LR-MS(API-ES): calculated for C₁₆H₁₁ClN₂O₂S 330.0, observed m/e 331.0 (M+H)⁺(R_(t) 3.10 min). The crude product was used in the next step withoutfurther purification.

Step B.6-Chloro-2-methanesulfonyl-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(49-2)

A solution of SEM-Cl (75.0 mg, 0.45 mmol) in THF (2 mL) was addeddropwise with stirring to an ice-bath (0° C.) cooled suspension ofCs₂CO₃ (195 mg, 0.600 mmol) in THF (3 mL) containing compound 49-1 (99.0mg, 0.300 mmol). The resulting suspension was stirred at 0° C. for 30min then allowed to warm up to rt, and stirred at rt for additional 30min. The suspension was than diluted with water (8 mL) and extractedwith EtOAc (5 mL, then 2 mL, twice). The organic layers were combinedand evaporated to dryness in vacuo to give the crude product asyellowish oil. LR-MS (API-ES): mixture of two N-SEM isomers, calculatedfor C₂₂H₂₅ClN₂O₃SSi 460.1, m/e (M+H)⁺ not observed, 433, 403 (100%)(R_(t) 3.83 min). The crude product was used in the next step withoutfurther purification.

Step C.3-[6-Chloro-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-2,2-dimethyl-propionicacid (49-3)

A 20 mL scintillation vial equipped with a septum cap and a magneticstirring bar was charged under N₂ with NaH (18.0 mg, 60% suspension inmineral oil, 0.45 mmol). In a separate vial, a solution of3-hydroxy-2,2-dimethyl-propionic acid methyl ester (79.0 mg, 0.600 mmol)in THF (2.0 mL) was combined with a solution of compound 49-2 (138.0 mg,0.300 mmol), and added dropwise to the 20 mL scintillation vialcontaining NaH. The resulting mixture was stirred at rt for 5 min, thencooled in a ice bath (0° C.) and quenched by a dropwise addition ofwater (6 mL). The mixture was allowed to warm up to rt and stirring wasmaintained for 5 min. The mixture was acidified with 5% aqueous HCl andextracted with EtOAc (three times, 3 mL). The organic layers werecombined and evaporated to dryness in vacuo. The residue was dissolvedin ACN (4 mL) and added to a vial containing 5% aqueous LiOH (1 mL). Theresulting mixture was stirred at 65° C. for 1 h, then acidified with 5%aqueous HCl and extracted with EtOAc (three times, 3 mL). The organiclayers were combined and evaporated to dryness in vacuo. The crudeproduct was used in the next step without further purification. LR-MS(API-ES): mixture of two N-SEM isomers, calculated for C₂₆H₃₁ClN₂O₄Si498.2, observed m/e 499.0 (M+H)⁺ (R_(t) 3.78. 3.87 min).

Step D.3-(6-Chloro-5-phenylethynyl-1H-benzoimidazol-2-yloxy)-2,2-dimethyl-propionicacid (49-4)

In a 4 mL vial, compound 49-3 (86.0 mg, 0.173 mmol) was dissolved in 9:1TFA/water (3 mL) and stirred at 65° C. for 10 min. The solution was thenevaporated to dryness in vacuo to give oily residue, which was dissolvedin DMSO (1 mL), filtered and purified by reverse-phase HPLC to give theformate salt of the title compound. LR-MS (API-ES): calculated forC₂₀H₁₇ClN₂O₃ 368.1, observed m/e 369.2 (M+H)⁺ (R_(t) 1.26 min).

Example 50 3-(6-Chloro-5-phenyl-1H-benzimidazol-2-yl)-propionic acid

3-(6-Chloro-5-phenyl-1H-benzimidazol-2-yl)-propionic acid

A 4 mL vial with a septum cap and a stirring bar was charged withphenylboronic acid (4.5 mg, 0.037 mmol) and Pd(PPh₃)₄ (2.0 mg, 5 mol %)and was purged briefly with N₂. A solution of3-(5-bromo-6-chloro-1H-benzimidazol-2-yl)-propionic acid methyl ester(Intermediate 9, 10.0 mg, 0.032 mmol) in DME (200 uL) was added to thevial, followed 1M aqueous K₂CO₃ (100 uL). The resulting mixture wasstirred at 85° C. for 10 h. The mixture was allowed to cool down to rt,and was partitioned with EtOAc (1 mL) and 10% aqueous AcOH (1 mL). Theorganic layer was separated and evaporated to dryness in vacuo. Theresulting oily residue was dissolved in DMSO (1.0 mL), filtered andpurified by reverse-phase HPLC to give the title compound. LR-MS(API-ES): calculated for C₁₆H₁₃ClN₂O₂ 300.0, observed m/e 301.0 (M+H)⁺(R_(t) 2.42 min).

Example 51 3-(5-Biphenyl-4-yl-6-chloro-1H-benzimidazol-2-yl)-propionicacid

3-(5-Biphenyl-4-yl-6-chloro-1H-benzimidazol-2-yl)-propionic acid

The title compound was prepared by procedure described in Example 50 bysubstituting phenylboronic acid with biphenyl-4-boronic acid. LR-MS(APT-ES): calculated for C₂₂H₁₇ClN₂O₂ 376.1, observed m/e 377.0 (M+H)⁺(R_(t) 3.02 min).

Example 52

[6-Chloro-5-(1H-indol-5-yl)-1H-benzoimidazol-2-ylsulfanyl]acetic acid

A mixture of ethyl 2-(6-chloro-5-iodo-1H-benzo[d]imidazol-2-ylthio)acetate (Intermediate 8; 0.15 g, 0.38 mmol), 5-indoylboronic acid (0.091g, 0.57 mmol), PdCl(dppf) (0.013 g, 0.019 mmol), K₂CO₃ (0.163 g, 1.2mmol), 3 mL of toluene and 1 mL of H₂O was heated to 130° C. for 10minutes using a microwave reactor. LCMS indicated incomplete reaction;therefore, the mixture was heated to 140° C. for 15 min using amicrowave reactor. The crude mixture was diluted with 20 mL of 1:1EtOAc:H₂O. The aqueous layer was collected and acidified to ˜pH=1 with1M HCl. Then the title compound was extracted using EtOAc. The organicfractions were combined, dried over MgSO₄ and concentrated in vacuo.This crude material was purified by HPLC using 30-80% acetonitrile-H₂Owith 0.05% TFA and lyophilized to afford the title compound as whitesolid. ¹H NMR (DMSO-d6) δ 11.17 (1H, s), 7.61 (1H, s), 7.55 (1H, s),7.44 (1H, d, J=8.5 Hz), 7.399-7.39 (2H, m), 7.13 (1H, d, J=8.5), 6.47(1H, s), 4.17 (2H, s); LRMS (API-ES) m/e for C₁₇H₁₂ClN₃O₂S (M+H)⁺, calcd357.82, found 358.4. Anal. Calcd for C₁₇H₁₂ClN₃O₂S+2.2H₂O+0.3 TFA: C,48.97; H, 3.90; N, 9.73. Found: C, 48.59; H, 3.54; N, 9.38.

Example 53

[6-Chloro-5-(1-methyl-indol-5-yl)-1H-benzoimidazol-2-ylsulfanyl]aceticacid

A mixture of ethyl2-(6-chloro-5-iodo-1H-benzo[d]imidazol-2-ylthio)acetate (Intermediate 8;0.15 g, 0.38 mmol), 1-methyl-5-indoylboronic acid (0.099 g, 0.57 mmol),PdCl(dppf) (0.013 g, 0.019 mmol), K₂CO₃ (0.163 g, 1.2 mmol), 3 mL oftoluene and 1 mL of H₂O was heated to 130° C. for 10 minutes using amicrowave reactor. LCMS indicated complete reaction. The crude mixturewas diluted with 20 mL of 1:1 EtOAc:H₂O. The aqueous layer was collectedand acidified to ˜pH=1 with 1M HCl. Then the title compound wasextracted using EtOAc. The organic fractions were combined, dried overMgSO₄ and concentrated in vacuo. This crude material was purified byHPLC using 30-80% acetonitrile-H₂O with 0.05% TFA and lyophilized toafford the title compound as an off-white solid. ¹H NMR (DMSO-d6) δ 7.61(1H, s), 7.56 (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.39 (1H, s), 7.37 (1H,d, J=3 Hz), 7.20 (dd, J=8.5, 3.0 Hz), 6.46 (1H, s), 4.17 (2H, s), 3.52(3H, s); LRMS (API-ES) m/e for C₁₈H₁₄ClN₃O₂S (M+H)⁺, calcd 371.85, found372.1. Anal. Calcd for C₁₈H₁₄ClN₃O₂S+2H₂O+0.5 TFA: C, 49.09; H, 4.01; N,9.04. Found: C, 49.33; H, 3.72; N, 8.76.

TABLE 6 Examples 54-86 in Table 6 were prepared following the proceduresdescribed in Examples 52 and 53 and using the appropriate startingmaterials. Example LCMS No. Structure (M + H)+ 54

385.4 55

359.1 56

344.1 57

344.1 58

401.1 59

372.1 60

402.1 61

404.4 62

405.4 63

375.1 64

423.1 65

409.4 66

358.4 67

377.1 68

423.1 69

379.4 70

388.1 71

405.4 72

402.1 73

397.1 74

389.4 75

387.1 76

400.1 77

436.4 78

429.1 79

398.9 80

374.4 81

387.1 82

414.1 83

400.1 84

365.4 85

367.4 86

381.4

Biological Example 1 AMPKSAMSF In Vitro AMPK Activation Assay

The recombinant human AMPK complex 1 (containing α1β1γ1) was obtainedfrom baculovirus expression system. Recombinant viruses were generatedby cotransfection of AMPK/pBacPak9 clones with Baculogold baculovirusDNA (Pharmingen) in spodoptera frugiperda 21 cells according to themanufacturer's instructions. Each round of virus amplification wasperformed for 5 days in Grace's medium containing 10% serum. Virus thathad been subjected to three rounds of amplification was used for allprotein production procedures. To express the AMPK complex, sf21 cellswere adapted to serum free medium (SF900 II, Invitrogen) by sequentialdilution from serum containing stocks into SF900II medium and maintainedin shaker flasks at 90 rpm at 27° C. The recombinant AMPK enzyme complexwas produced by triple infection, one recombinant virus for each of thesubunits, in sf21 cells under serum free conditions. Cells were infectedin log phase, 1×10⁶ cells/ml, at a multiplicity of infection of ˜5.Cells were harvested by centrifugation at 10,000×g for 15 minutes after72 hours of infection with viruses. The insect cell pellet from 2 litersof culture was resuspended in 50 ml lysis buffer (20 mM Tris-HCl, 50 mMNaCl, 50 mM NaF, 30 mM Na PPi, 0.25 M sucrose, 10 mM ZnCl₂, 2 mM DTT,0.4 mg/ml digitonin) and subjected to two cycles of freeze-thaw lysis ina dry-ice ethanol bath. Insoluble material was removed by centrifugationat 10,000×g and the supernatant was fractionated with use ofpolyethylene glycol (PEG). The protein fraction precipitating between2.5 and 6% PEG was used for further purification using a Blue-Sepharosestep (Zhou et al, J. Clin. Invest. 108, 1167-1174, 2001).

The total in vitro AMPK activation assay volume is 50 μl in a 96-wellplate. The reaction mixture contained 100 μM ATP (0.5 μCi ³³P-ATP perreaction), and 50 μM SAMS (HMRSAMSGLHLVKRR) in a buffer (20 mM HEPES, pH7.0, 5 mM MgCl₂, 0.01% Brij35). The reaction was initiated with additionof the enzyme. After 30-minute incubation at 30° C., the reaction wasstopped by addition of 80 μl 1% H₃PO₄. Aliquots (100 μl) weretransferred to 96-well MultiScreen plates (MAPHNOB50; Millipore Corp.,Bedford, Mass., USA). The plate was washed three times with 1% H₃PO₄followed by detection in a Top-count. The counts per minute from thebasal activity (the reaction without activator) was subtracted from eachwell and the data were expressed as % maximum AMP activation followed byEC₅₀ calculation. The % maximum AMP activation for selected compounds isprovided in the table below.

The compounds of the present invention have greater than 40% maximum AMPactivation of human AMPK complex 1 (containing α1β1γ1), and EC₅₀ valuesof less than 10 micromolar.

The compounds of Examples 1-86 were tested in the in vitro AMPKactivation assay using recombinant human AMPK complex 1 (containingα1β1γ1) and found to have EC₅₀ values of less than 10 micromolar andgreater than 40% maximum AMP activation. Preferred compounds of thepresent invention were found to have EC₅₀ values of less than 0.5micromolar in the in vitro AMPK activation assay using recombinant humanAMPK complex 1.

Maximum AMP Activation for Selected Compounds % Maximum AMP Activationof human AMPK Example No. Complex 1 EC₅₀ (nM) 1 269 259 2 197 90 6 15013 18 259 248 45 239 160 46 177 128 47 157 97 48 147 130 59 205 100 66279 282

Biological Example 2 Inhibition of Fatty Acid Synthesis (FAS) by AMPKActivators in db/+Mice

To determine the effect of AMPK activators on Fatty Acid Synthesis (FAS)in the liver, the effect of oral pre-dosing of compounds on the amountof ³H incorporated into hepatic triglyceride is determined as describedby Sakurai T, Miyazawa S, Shindo Y, and T. Hashimoto (Biochim BiophysActa. 1974 Sep. 19; 360 (3):275-88). Briefly, mice (db/+, JacksonLaboratory, Maine) are orally dosed with AMPK activators at time=−8 h.Then at time=−1 h, mice are injected with 0.5 ml of 0.15 M NaClcontaining 0.2 mCi of ³H water per 100 g of body weight. At time 0, miceare sacrificed via cervical dislocation and livers are harvested for FASanalysis. To analyze livers for FAS, samples of liver are heated at 90°C. for 5 hours in a 4 M KOH/50% ethanol solution. Then the alkalinehydrolysate of liver is extracted with hexane and acidified to a pH <2with 10 M H₂SO₄. The fatty acids of liver are then extracted fromacidified hydrolysate with additional hexane, dried down with a streamof warm air, then re-suspended in scintillation fluid, and counted on abeta counter. The amount of fatty acids synthesized per gram of liver iscalculated based on the amount of ³H incorporated into hepatictriglyceride. The amount of ³H radiolabelled fatty acids synthesized inmice with treated with an AMPK activator is significantly less than theamount of ³H radiolabelled fatty acids synthesized in the control mice.

Biological Example 3 In Vivo Study for Therapy with an AMPK Activator inMice (Glucose Tolerance Test)

DIO mice are treated simultaneously with an effective dose of anAMPK-activated protein kinase activator.

Materials and Methods: Male C57BL/6NT mice (Taconic, 16-18 weeks old atthe beginning of the drug administration) are used. Mice are given waterand high fat diet D12492 (Research Diet Inc.) ad libitum. They are keptin an animal room which is maintained at 23±2 C temperature, 55±15%relative humidity and on a 12-hr light-dark cycle (7:00-19:00) during aquarantine and acclimatization period of 1 week. Animals are thenadministered vehicle (5 ml/kg of 0.5% methylcellulose in distilledwater) by oral gavage twice-daily at 9 AM and 5 PM. After 9 days, stablebody weight is observed. The following day (day −1), the mice are fastedfor 4 hours and tail bled to determine the glucose and insulin levels.Animals are sorted into groups based on plasma glucose, insulin levelsand body weight (n=8). The body weight and food in the hopper arerecorded on day 0 before compound dosing is initiated. One of the groupsis orally administered vehicle while the second group is administered anAMPK-activated protein kinase activator of the present invention at adose of 30 mg/kg (5 ml/kg) twice-daily for 12 days by gavage. Bodyweight and food intake are measured every other day. On day 5, theanimals are fasted 4 hours for measuring plasma glucose and insulinlevels after morning dosing. At day 12, body weight and food intake aremeasured and animals receive their last morning dose. Mice again arefasted 4 hours, blood is collected at a set time point (t=0 min), andthen challenged with dextrose orally (2 g/kg) Plasma glucose and insulinlevels are determined from tail bleeds taken at 20 and 90 minutes afterdextrose challenge. The plasma glucose and insulin excursion profilefrom t=0 to t=90 min is used to integrate an area under the curve (AUC)for each treatment. Percent inhibition values for each treatment aregenerated from the AUC data normalized to the C57BL/6NT mice feed withD7012. Preferred compounds of the present invention significantly reduceday 12 glucose and/or insulin AUC during the Oral Glucose Tolerance Testafter an oral dose in the range of 0.1 to 100 mg/kg.

Biological Example 4 Acute Food Intake Studies in Diet Induced Obese(DIO) Mice: General Procedure

Adult DIO mice are used in these studies. After at least 2 days ofacclimation to the vivarium conditions (controlled humidity andtemperature, lights on for 12 hours out of 24 hours) food (D12492(Research Diet Inc.) is removed from rodent cages. An AMPK activator ofthe present invention or the vehicle is administered orally,intraperitoneally, subcutaneously or intravenously before the return ofa known amount of food to cage. The optimal interval between dosing andfood presentation is based on the half-life of the compound based onwhen brain concentrations of the compound is the highest. Food remainingis measured at several intervals. Food intake is calculated as grams offood eaten per gram of body weight within each time interval and theappetite-suppressant effect of the AMPK activator is compared to theeffect of the vehicle. The food intake of mice treated with an AMPKactivator is significantly less than the food intake of control mice.

Biological Example 5 Chronic Weight Reduction Studies in Diet InducedObese (DIO) Mice: General Procedure

Adult DIO mice are used in these studies. Upon or soon after weaning,rats or mice are made obese due to exclusive access to diets containingfat and sucrose in higher proportions than in the control diet. The dietused to induce obesity is Research Diets D12451 chow (45% fat). Therodents ingest chow until they are significantly heavier and have ahigher proportion of body fat than control diet rats, often 9 weeks. Therodents receive injections (1 to 4 per day) or continuous infusions ofan AMPK activator of the present invention or the vehicle either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effect of the AMPKactivator of the present invention is compared to the effect of thevehicle. The weight loss of mice treated with an AMPK activator issignificantly greater than the weight loss of control mice.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is absent orselected from: (1) —S—, (2) —O—, (3) —NH—, (4) —C(O)—, (5) —NHC(O)—, (6)—C(O)NH—, (7) —NHSO₂—, (8) —SO₂NH—, and (9) —CO₂—, wherein NH isunsubstituted or substituted with 1 substituent selected from:—C₁₋₆alkyl, —CO₂H, —CO₂C₁₋₆alkyl, —COC₁₋₆alkyl, phenyl and —CH₂-phenyl;Y is selected from: (1) —CH₂—, (2) —CH₂—CH₂—, (3) —CH₂—CH₂—CH₂—, (4)—CHF—, and (5) —CF₂—, wherein each CH₂ and CHF is unsubstituted orsubstituted with 1 or 2 substituents selected from Rb; Z is selectedfrom: (1) —CO₂H, (2) —C(O)NH₂, (3) tetrazole, and (4) dihydrooxadiazole,wherein each dihydrooxadiazole and tetrazole is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from R^(c); R¹ isindependently selected from: 1) —C₃₋₁₀cycloalkyl, 2)—C₃₋₇cycloalkyl-aryl, 3) —C₃₋₇cycloalkyl-heteroaryl, 4)—C₄₋₁₀cycloalkenyl, 5) —C₄₋₇cycloalkenyl-aryl, 6)—C₄₋₇cycloalkenyl-heteroaryl, 7) aryl, 8) biphenyl, 9) -heteroaryl, 10)—C₂₋₆alkenyl-alkyl, 11) —C₂₋₆alkenyl-aryl, 12) —C₂₋₆alkenyl-heteroaryl,13) —C₂₋₆alkenyl-C₃₋₇cycloalkyl, 14) —C₂₋₆alkenyl-C₃₋₇cycloalkenyl, 15)—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, 16)—C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl, 17) —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,18) —C₂₋₆alkynyl-alkyl, 19) —C₂₋₆alkynyl-aryl, 20)—C₂₋₆alkynyl-heteroaryl, 21) —C₂₋₆alkynyl-C₃₋₇cycloalkyl, 22)—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, 23) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,24) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and 25) —(CH₂)_(p)C(O)phenyl,wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl,alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein eachcycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl,aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is selected fromthe group consisting of: halogen, —CN, —CF₃, —C₂₋₆alkenyl and—C₂₋₆alkynyl, wherein each alkenyl and alkynyl is unsubstituted orsubstituted with 1, 2 or 3 substituents selected from: halogen, CF₃,—OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂; orR² represents —C₁₋₆alkyl substituted with 1, 2 or 3 substituentsselected from: halogen, CF₃, —OH, —NH₂, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and—N(C₁₋₆alkyl)₂; R³ is hydrogen; R⁴ is hydrogen; R⁵ is selected from: (1)hydrogen, (2) —C₁₋₆alkyl, (3) —CH₂CO₂H, and (4) —CH₂CO₂C₁₋₆alkyl; eachR^(a) is independently selected from the group consisting of: (1)halogen, (2) oxo, (3) —(CH₂)_(m)OH, (4) —(CH₂)_(m)N(R^(j))₂, (5)—(CH₂)_(m)NO₂, (6) —(CH₂)_(m)CN, (7) —C₁₋₆alkyl, (8) —(CH₂)_(m)CF₃, (9)—(CH₂)_(m)OCF₃, (10) —OCH₂OC₁₋₆alkyl, (11) —O-aryl, (12) —OCH₂-aryl,(13) —(CH₂)_(m)C(═N—OH)N(R^(j))₂, (14) —(CH₂)_(m)OC₁₋₆alkyl, (15)—(CH₂)_(m)—O-aryl, (16) —(CH₂)_(m)SC₁₋₆alkyl, (17)—(CH₂)_(m)S(O)C₁₋₆alkyl, (18) —(CH₂)_(m)S(O)₂C₁₋₆alkyl, (19)—(CH₂)_(m)NHS(O)₂C₁₋₆alkyl, (20) —(CH₂)_(m)C(O)R^(f), (21)—(CH₂)_(m)C(O)N(R^(j))₂, (22) —(CH₂)_(m)N(R^(j))C(O)R^(f), (23)—(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂, (24) —(CH₂)_(m)CO₂H, (25)—(CH₂)_(m)OC(O)H, (26) —(CH₂)_(m)CO₂R^(f), (27) —(CH₂)_(m)OC(O)R_(f),(28) —(CH₂)_(m)C₃₋₇cycloalkyl, (29) —(CH₂)_(m)C₃₋₇cycloalkenyl, (30)—(CH₂)_(m)C₂₋₆cycloheteroalkyl, (31) —(CH₂)_(m)C₂₋₆cycloheteroalkenyl,(32) —(CH₂)_(m)aryl, and (33) —(CH₂)_(m)heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl, andeach alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen,—CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl,CH₂-phenyl, heteroaryl and CH₂heteroaryl; each R^(b) is independentlyselected from: (1) hydrogen, (2) —C₁₋₆alkyl, (3) halogen, (4) —OH, (5)—NO₂, (6) —NH₂, (7) —NH(C₁₋₆alkyl), (8) —N(C₁₋₆alkyl)₂, (9) —OC₁₋₆alkyl,(10) —CF₃, (11) —CN, (12) —SO₂C₁₋₆alkyl, and (13) —(CH₂)_(q)CON(R^(e))₂,wherein each CH₂ is unsubstituted or substituted with 1 or 2 halogens,and wherein each alkyl is unsubstituted or substituted with 1, 2 or 3halogens; each R^(c) is independently selected from: (1) halogen, (2)oxo, (3) —(CH₂)_(r)OH, (4) —(CH₂)_(r)N(R^(e))₂, (5) —(CH₂)_(r)CN, (6)—C₁₋₆alkyl, (7) —CF₃, (8) —C₁₋₆alkyl-OH, (9) —OCH₂OC₁₋₆alkyl, (10)—(CH₂)_(r)OC₁₋₆alkyl, (11) —OCH₂aryl, (12) —(CH₂)_(r)SC₁₋₆alkyl, (13)—(CH₂)_(r)C(O)R^(f), (14) —(CH₂)_(r)C(O)N(R^(e))₂, (15) —(CH₂)_(r)CO₂H,(16) —(CH₂)_(r)CO₂R^(f), (17) —(CH₂)_(r)C₃₋₇cycloalkyl, (18)—(CH₂)_(r)C₂₋₆cycloheteroalkyl, (19) —(CH₂)_(r)aryl, and (20)—(CH₂)_(r)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and each alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN,—N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C3_(—)7cycloalkyl and heteroaryl; each R^(e), R^(g) andR^(h) is independently selected from: (1) hydrogen, and (2) C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂; each R^(j) is independentlyselected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4)—C(O)R^(i), and (5) —SO₂R^(i), wherein alkyl and cycloalkyl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂; each R^(f) and R^(i) is independently selected from:(1) C₁₋₆alkyl, (2) C₄₋₇cycloalkyl, (3) C₄₋₇cycloalkenyl, (4)C₃₋₇cycloheteroalkyl, (5) C₃₋₇cycloheteroalkenyl, (6) aryl, and (7)heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, and heteroaryl; n is 0, 1, 2, 3 or 4; mis 0, 1, 2, 3 or 4; p is 1; q is 0, 1, 2, 3 or 4; and r is 0, 1 or
 2. 2.The compound according to claim 1, wherein X is absent or selected from:—S— and —O—, or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 2, wherein X is selected from: —S— and —O—,or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 3, wherein Y is selected from: —CH₂— and —CH₂—CH₂—, whereineach —CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from Rb; or a pharmaceutically acceptable salt thereof.
 5. Thecompound according to claim 4, wherein Y is —CH₂—, wherein CH₂ isunsubstituted or substituted with 1 or 2 substituents selected fromR^(b); or a pharmaceutically acceptable salt thereof.
 6. The compoundaccording to claim 5, wherein Z is —CO₂H; or a pharmaceuticallyacceptable salt thereof.
 7. The compound according to claim 1, whereinR⁵ is hydrogen; or a pharmaceutically acceptable salt thereof.
 8. Thecompound according to claim 7, wherein R¹ is selected from: 1) aryl, 2)biphenyl, 3) heteroaryl, 4) —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, 5)—C₂₋₆alkynyl-aryl, 6) —C₂₋₆alkynyl-heteroaryl, 7)—C₂₋₆alkynyl-C₃₋₇cycloalkyl, 8) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, and9) —(CH₂)_(p)C(O)phenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, whereineach alkynyl is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloalkyl,cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromR^(a), and R² is halogen; and p is 1; or a pharmaceutically acceptablesalt thereof.
 9. The compound according to claim 8, wherein each R^(a)is independently selected from the group consisting of: (1) halogen, (2)—(CH₂)_(m)OH, (3) —N(R^(j))₂, (4) —NO₂, (5) —CN, (6) —C₁₋₆alkyl, (7)—CF₃, (8) —O-aryl, (9) —OCH₂-aryl, (10) —OC₁₋₆alkyl, (11) —SC₁₋₆alkyl,(12) —S(O)C₁₋₆alkyl, (13) —S(O)₂C₁₋₆alkyl, (14) —NHS(O)₂C₁₋₆alkyl, (15)—C(O)N(R^(j))₂, (16) —(CH₂)_(m)N(R^(j))C(O)R^(f), (17)—N(R^(j))C(O)N(R^(j))₂, (18) —CO₂H, (19) —C₂₋₆cycloheteroalkyl, (20)aryl, and (21) heteroaryl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: oxo, —(CH₂)₀₋₃OH,—CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, and wherein alkyl,cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2 or 3 substituents selected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl; or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 1 of structural formula Ib:

wherein: R¹ is selected from: (1) phenyl, (2) biphenyl, (3) heteroaryl,and (4) —C₂alkynyl-phenyl, wherein each phenyl and heteroaryl isunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from R^(a); R² is halogen; R³, R⁴ and R⁵ are hydrogen; X isselected from: —S— and —O—; Z is —CO₂H; each R^(a) is independentlyselected from the group consisting of: (1) —(CH₂)_(m)OH, (2) —C₁₋₆alkyl,(3) phenyl, and (4) heteroaryl, wherein each alkyl, phenyl andheteroaryl is unsubstituted or substituted with 1, 2 or 3 substituentsselected from: oxo, —(CH₂)₀₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl; each R^(b) is independently selected from:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with 1, 2 or 3 halogens; and s is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 10 selected from:

or a pharmaceutically acceptable salt thereof.
 12. A compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 13. A composition comprising a compound according toclaim 1, a compound selected from simvastatin, ezetimibe, taranabant andsitagliptin; and a pharmaceutically acceptable carrier.